Anxiolytic agents with reduced sedative and ataxic effects

ABSTRACT

Orally active benzodiazepine derivatives and their salts are disclosed. These compounds and their salts have anxiolytic and anticonvulsant activity with reduced sedative/hypnotic/muscle relaxant/ataxic effects.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 10/402,538filed on Mar. 28, 2003 now U.S. Pat. No. 7,119,196, which claims benefitof U.S. Provisional Patent Application No. 60/368,408 filed Mar. 28,2002, both of which are incorporated herein in its entirety as if fullyset forth herein.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with Government support under NIMH grant numberMH46851. The Government has certain rights to this invention.

BACKGROUND OF THE INVENTION

The present invention relates to a class of benzodiazepine derivativeswhich possess anxiolytic activity with decreased sedative, hypnotic, andataxic side effects.

The most frequently prescribed medication for treatment of anxietydisorders (such as phobias, obsessive compulsive disorders) and seizuredisorders are benzodiazepines such as diazepam (Valium), triazolam(Halcion), midazolam (Versed), lorazepam (Ativan), chlordiazepoxide(Librium), alprazolam (Xanax), and other benzodiazepine-basedmedications. However, these benzodiazepine-based medications have sideeffects such as drowsiness, sedation, motor incoordination, memoryimpairment, potentiation of effects of alcohol, tolerance anddependence, and abuse potential. Buspirone, tandospirone, and otherserotonergic agents have been developed as anxiolytics with apotentially reduced profile of side effects. However, while thesemedications do show a reduced profile of side effects, they have othercharacteristics which make them less than ideal for treatment of anxietydisorders. In some cases, these agents cause anxiety before atherapeutic dose can be obtained or require dosing of the drug forseveral days before a therapeutic effect is seen. Development ofanxiolytics with even fewer side effects is desired.

Receptors for the major inhibitory neurotransmitter, gamma-aminobutyricacid (GABA), are divided into three main classes: (1) GABA_(A)receptors, which are members of the ligand-gated ion channelsuperfamily; (2) GABA_(B) receptors, which may be members of theG-protein linked receptor superfamily; and (3) GABA_(C) receptors, alsomembers of the ligand-gated ion channel superfamily, but theirdistribution is confined to the retina. Benzodiazepine receptor ligandsdo not bind to GABA_(B) and GABA_(C) receptors. Since the first cDNAsencoding individual GABA_(A) receptor subunits were cloned the number ofknown members of the mammalian family has grown to 21 including α, β,and γ subunits (6α, 4β, 4γ, 1δ, 1ε, 1π, 1θ, and 3ρ).

Subtype assemblies containing an α1 subunit (α1β2γ2) are present in mostareas of the brain and are thought to account for 40-50% of GABA_(A)receptors in the rat. Subtype assemblies containing α2 and α3 subunitsrespectively are thought to account for about 25% and 17% GABA_(A)receptors in the rat. Subtype assemblies containing an α5 subunit(α5β3γ2) are expressed predominately in the hippocampus and cortex andare thought to represent about 4% of GABA_(A) receptors in the rat.

A characteristic property of all known GABA_(A) receptors is thepresence of a number of modulatory sites, one of which is thebenzodiazepine binding site. The benzodiazepine binding site is the mostexplored of the GABA_(A) receptor modulatory sites, and is the sitethrough which benzodiazepine-based anxiolytic drugs exert their effect.Before the cloning of the GABA_(A) receptor gene family, thebenzodiazepine binding site was historically subdivided into twosubtypes, BENZODIAZEPINE1 and BENZODIAZEPINE2, on the basis ofradioligand binding studies on synaptosomal rat membranes. TheBENZODIAZEPINE1 subtype has been shown to be pharmacologicallyequivalent to a GABA_(A) receptor comprising the α1 subunit incombination with a β subunit and γ2. This is the most abundant GABA_(A)receptor subtype, and is believed to represent almost half of allGABA_(A) receptors in the brain, as stated.

Two other major populations are the (α2β2/3γ2 and α3β2/3γ2/3 subtypes.Together these constitute approximately a further 35% of the totalGABA_(A) receptor population. Pharmacologically this combination appearsto be equivalent to the BENZODIAZEPINE2 subtype as defined previously byradioligand binding, although the BENZODIAZEPINE2 subtype may alsoinclude certain α5-containing subtype assemblies. The physiological roleof these subtypes has hitherto been unclear because no sufficientlyselective agonists or antagonists were known.

It is now believed that agents acting as benzodiazepine agonists atGABA_(A)/α2, GABA_(A)/α3, and/or GABA_(A)/α5 receptors, will possessdesirable anxiolytic properties. Compounds which are modulators of thebenzodiazepine binding site of the GABA_(A) receptor by acting asbenzodiazepine agonists are referred to hereinafter as “GABA_(A)receptor agonists.” The GABA_(A)/α1-selective (α1β2γ2) agonists alpidemand zolpidem are clinically prescribed as hypnotic agents, suggestingthat at least some of the sedation associated with known anxiolyticdrugs which act at the BENZODIAZEPINE 1 binding site is mediated throughGABA_(A) receptors containing the α1 subunit. Accordingly, it isconsidered that GABA_(A)/α2, GABA_(A)/α3, and/or GABA_(A)/α5 receptoragonists rather than GABA_(A)/α1 receptors will be effective in thetreatment of anxiety with a reduced propensity to cause sedation. Forexample, QH-ii-066 binds with high affinity to GABA_(A)/α0.5 receptors(Ki<10 nM), intermediate affinity to GABA_(A)/α2 and GABA_(A)/α3 (Ki<50nM), and lower affinity to GABA_(A)/α1 receptors (Ki>70 nM), unlikediazepam which binds with high affinity to all four diazepam-sensitiveGABA_(A) receptors (Ki<25 nM), as disclosed in Huang, et al., J. Med.Chem. 2000, 43, 71-95. Also, agents which are antagonists or inverseagonists at α1 receptors might be employed to reverse sedation orhypnosis caused by α1 agonists.

Since the compounds of the present invention exhibit increased agonistefficacy at only a few GABA_(A) types of receptors and/or selectiveefficacy at one or more ion channels and have been shown to be effectivein animal models of anxiety and seizures, with reduced severity and/orincidence of side effects, they are useful in the treatment and/orprevention of a variety of disorders of the central nervous system. Suchdisorders include anxiety disorders, such as panic disorder with orwithout agoraphobia, agoraphobia without history of panic disorder,animal and other phobias including social phobias, obsessive-compulsivedisorder, general anxiety disorder, attention deficit disorders, stressdisorders including post-traumatic and acute stress disorder, andgeneralized or substance-induced anxiety disorder, neuroses,convulsions; migraine; depressive or bipolar disorders, for examplesingle episode or recurrent major depressive disorder, dysthymicdisorder, bipolar I and bipolar II manic disorders, and cyclothymicdisorder, psychotic disorders including schizophrenia.

SUMMARY OF THE INVENTION

In consideration of this situation, the problem to be solved by thepresent invention is to provide a medication which can be used for thetreatment of anxiety neurosis, general anxiety disorder, panic disorder,phobias, obsessive-compulsive disorders, schizophrenia, post-cardiactrauma stress disorders, depression disorders, psychosomatic disorders,and other psychoneurotic disorders, eating disorders, menopausaldisorders, infantile autism and other disorders, and also emesis withfewer side effects.

The present inventors engaged in repeated extensive studies to develop asuperior medication free from the above problems. They found that thecompounds of the present invention, that is, the novel benzodiazepinederivatives and their salts, have beneficial pharmacological andbehavioral effects, that is, the compounds of the present invention showanxiolytic and anticonvulsant activity with greatly decreased or nosedative/hypnotic/muscle relaxant/ataxic side effects.

The compounds described in the present invention have been synthesizedbased on a modified version of the computer modeling disclosed in Cook,et al J. Med. Chem., 1996, 39, 1928-1934. These compounds obtained bymodifying elements, described herein, of the known benzodiazepineagents, have increased binding selectivity for the GABA_(A)/α2,GABA_(A)/α3, and/or GABA_(A)/α5 receptors described above, and/oraltered efficacy at one or more GABA_(A) receptors described above,and/or altered selectivity at one or more ion channels. These compounds,which have been tested in animal models of anxiety in rats and seizuresin mice, and side effect models in rats, have been found to be orallyactive and have anxiolytic and anticonvulsant activity, with reducedseverity and/or incidence of side effects.

One object of the present invention is to identify medicationscontaining these benzodiazepine derivatives or their pharmaceuticallyacceptable salts as essential ingredients that are usable for thetreatment of anxiety neurosis, phobias, obsessive-compulsive disorders,panic disorder, generalized anxiety disorder, schizophrenia,post-cardiac trauma stress disorders, depression disorders,psychosomatic disorders, and other psychoneurotic disorders, eatingdisorders, menopausal disorders, infantile autism, and other disorders.

The present invention describes a class of benzodiazepine derivativeswhich possess desirable enhanced agonist efficacy at various GABA_(A)receptors and desirable behavioral profile with respect to anxiolyticand anticonvulsant efficacy and reduced side effect efficacy. Thecompounds in accordance with the present invention have agonist efficacyat the GABA_(A)/α2, GABA_(A)/α3, and GABA_(A)/α5 receptors. Thecompounds of this invention have anxiolytic and anticonvulsant effectswith decreased sedative-hypnotic activity.

The present invention provides a compound of formula I, or a salt orprodrug thereof,

wherein Y and Z are taken together with the two intervening carbon atomsto form a ring selected from phenyl and thienyl, which ring issubstituted at the C(7) position with at least the substituent —C≡C—R,where R is H, Si(CH₃)₃, t-butyl, isopropyl, methyl, or cyclopropyl; R₁is one of H, CH₃, C₂H₄N(C₂H₅)₂, CH₂CF₃, CH₂C≡CH, or an alkylcyclopropyl; R₂ is a substituted or unsubstituted at least partiallyunsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein ifsubstituted the substituent is one or more of F, Cl, Br, or NO₂ at the2′-position; and R₃ is one of H, OH, OCON(CH₃)₂, COOCH₃, or COOC₂H₅.Preferred compounds according to formula I include:

The invention provides in another aspect a compound of formula II, or asalt or prodrug thereof,

wherein Y and Z are taken together with the two intervening carbon atomsto form a ring selected from phenyl and thienyl, which ring issubstituted at the C(7) position with at least the substituent —C≡C—R,where R is H, Si(CH₃)₃, t-butyl, isopropyl, methyl, or cyclopropyl; R₁is one of H, CH₃, C₂H₄N(C₂H₅)₂, CH₂CF₃, CH₂C≡CH, or an alkylcyclopropyl; and R₂ is a substituted or unsubstituted at least partiallyunsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein ifsubstituted the substituent is one or more of F, Cl, Br, or NO₂ at the2′-position. Preferred compounds according to formula II include:

The present invention provides in yet another aspect a compound offormula III, or a salt or prodrug thereof,

wherein Y and Z are taken together with the two intervening carbon atomsto form a ring selected from phenyl and thienyl, which ring issubstituted at the C(7) position with at least the substituent —C≡C—R,where R is H, Si(CH₃)₃, t-butyl, isopropyl, methyl, or cyclopropyl; andR₂ is a substituted or unsubstituted at least partially unsaturated 5 or6 membered cyclic or heterocyclic ring, wherein if substituted thesubstituent is one or more of F, Cl, Br, or NO₂ at the 2′-position.Preferred compounds according to the formula III include:

Further, the present invention provides a compound of formula IV, or asalt or prodrug thereof.

wherein R is H, Si(CH₃)₃, t-butyl, isopropyl, methyl, or cyclopropyl; R₁is one of H, CH₃, C₂H₄N(C₂H₅)₂, CH₂CF₃, CH₂C≡CH, or an alkylcyclopropyl; R₂ is a substituted or unsubstituted at least partiallyunsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein ifsubstituted the substituent is one or more of F, Cl, Br, or NO₂ at the2′-position; and A is an ethoxide or a propoxide. Preferred compoundsaccording to the formula IV include:

In a still further aspect, the present invention provides a compound offormula V, or a salt or prodrug thereof,

wherein Y and Z are taken together with the two intervening carbon atomsto form a ring selected from phenyl and thienyl, which ring issubstituted at the C(8) position with at least the substituent —C≡C—R,where R is H, Si(CH₃)₃, t-butyl, isopropyl, methyl, or cyclopropyl; R₁is one of H, CH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂C≡CH, an alkyl, orcyclopropyl; R₂ is a substituted or unsubstituted at least partiallyunsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein ifsubstituted the substituent is one or more of F, Cl, Br, or NO₂ at the2′-position; and R₅ is a branched or straight chain C₁ to C₄ halogenatedor unhalogenated alkyl or a methyl cyclopropyl. Preferred compoundsaccording to formula V include:

In yet another aspect, the present invention provides a compound offormula VI, or a salt or prodrug thereof,

wherein Y and Z are taken together with the two intervening carbon atomsto form a ring selected from phenyl and thienyl, which ring issubstituted at the C(8) position with at least the substituent —C≡C—R,where R is H, Si(CH₃)₃, t-butyl, isopropyl, methyl, or cyclopropyl; R₁is one of H, CH₃, CF₃, CH₂CH₃, CH₂CF₃, or cyclopropyl; R₂ is asubstituted or unsubstituted at least partially unsaturated 5 or 6membered cyclic or heterocyclic ring, wherein if substituted thesubstituent is one or more of F, Cl, Br, or NO₂ at the 2′-position; andR₆ is a branched or straight chain C₁ to C₄ alkyl or a methylcyclopropyl. Preferred compounds according to formula VI include:

The present invention also provides a compound of formula VII, or a saltor prodrug thereof,

wherein Y and Z are taken together with the two intervening carbon atomsto form a ring selected from phenyl and thienyl, which ring issubstituted at the C(8) position with at least the substituent —C≡C—R,where R is H, Si(CH₃)₃, t-butyl, isopropyl, methyl, or cyclopropyl; andR₂ is a substituted or unsubstituted at least partially unsaturated 5 or6 membered cyclic or heterocyclic ring, wherein if substituted thesubstituent is one or more of F, Cl, Br, or NO₂ at the 2′-position.Preferred compounds according to formula VII include:

The present invention still further provides a compound of formula VIII,or a salt or prodrug thereof,

wherein Y and Z are taken together with the two intervening carbon atomsto form a ring selected from phenyl and thienyl, which ring issubstituted at the C(8) position with at least the substituent —C≡C—R,where X is N or CH, where R is H, Si(CH₃)₃, t-butyl, isopropyl, methyl,or cyclopropyl; R₁ is H, CH₃, CF₃, CH₂CH₃, CH₂CF₃, or cyclopropyl; R₂ isa substituted or unsubstituted at least partially unsaturated 5 or 6membered cyclic or heterocyclic ring, wherein if substituted thesubstituent is one or more of F, Cl, Br, or NO₂ at the 2′-position.Preferred compounds according to formula VIII include:

Yet another aspect of the present invention provides a compound offormula IX, or a salt or prodrug thereof,

wherein n is 0 to 4; Y and Z are taken together with the two interveningcarbon atoms to form a ring selected from phenyl and thienyl, which ringis substituted at the C(8) position with at least the substituent—C≡C—R, where R is H, Si(CH₃)₃, t-butyl, isopropyl, methyl, orcyclopropyl; Y′ and Z′ are taken together with the two interveningcarbon atoms to form a ring selected from phenyl and thienyl, which ringis substituted at the C(8)′ position with at least the substituent—C≡C—R′, where R′ is H, Si(CH₃)₃, t-butyl, isopropyl, methyl, orcyclopropyl; R₁ and R₁′ are independently one of H, CH₃, CF₃, CH₂CF₃,CH₂CH₃, or cyclopropyl; and R₂ and R₂′ are independently a substitutedor unsubstituted at least partially unsaturated 5 or 6 membered cyclicor heterocyclic ring, wherein if substituted the substituent is one ormore of F, Cl, Br, or NO₂ at the 2′-position. Preferred compoundsaccording to formula IX include:

A still further aspect of the present invention provides a compound offormula X, or a salt or prodrug thereof,

wherein Y and Z are taken together with the two intervening carbon atomsto form a ring selected from phenyl and thienyl, which ring issubstituted at the C(8) position with at least the substituent —C≡C—R,where R is H, Si(CH₃)₃, t-butyl, isopropyl, methyl, or cyclopropyl; Y′and Z′ are taken together with the two intervening carbon atoms to forma ring selected from phenyl and thienyl, which ring is substituted atthe C(8)′ position with at least the substituent —C≡C—R′ where R′ is H,Si(CH₃)₃, t-butyl, isopropyl, methyl, or cyclopropyl; R₁ and R₁′ areindependently one of H, CH₃, CF₃, CH₂CH₃, CH₂CF₃, or cyclopropyl; R₂ andR₂′ are independently a substituted or unsubstituted at least partiallyunsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein ifsubstituted the substituent is one or more of F, Cl, Br, or NO₂ at the2′-position; and B is O or NH and wherein —BCH₂B— is optionally replacedwith —N(R₇)—N(R₇)—, where R₇ is one of H, CH₃, alkyl, or cycloalkyl.Preferred compounds according to formula X include:

The present invention further provides a compound of formula XI, or asalt or prodrug thereof,

wherein n is 1 or 2; wherein Y and Z are taken together with the twointervening carbon atoms to form a ring selected from phenyl andthienyl, which ring is substituted at the C(8) position with at leastthe substituent —C≡C—R, where R is H, Si(CH₃)₃, t-butyl, isopropyl,methyl, or cyclopropyl; Y′ and Z′ are taken together with the twointervening carbon atoms to form a ring selected from phenyl andthienyl, which ring is substituted at the C(8)′ position with at leastthe substituent —C≡C—R′, where R′ is H, Si(CH₃)₃, t-butyl, isopropyl,methyl, or cyclopropyl; R₁ and R₁′ are independently one of H, CH₃, CF₃,CH₂CH₃, CH₂CF₃, or cyclopropyl; R₂ and R₂′ are independently asubstituted or unsubstituted at least partially unsaturated 5 or 6membered cyclic or heterocyclic ring, wherein if substituted thesubstituent is one or more of F, Cl, Br, or NO₂ at the 2′-position; andB is O, NH, or —N(R₇)—N(R₇)—, where R₇ is one of H, CH₃, alkyl, orcycloalkyl. Preferred compounds according to formula XI include:

Yet another aspect of the present invention provides a compound offormula XII, or a salt or prodrug thereof,

wherein n is 0 to 4; Y and Z are taken together with the two interveningcarbon atoms to form a ring selected from phenyl and thienyl, which ringis substituted at the C(7) position with at least the substituent—C≡C—R, where R is H, Si(CH₃)₃, t-butyl, isopropyl, methyl, orcyclopropyl; Y′ and Z′ are taken together with the two interveningcarbon atoms to form a ring selected from phenyl and thienyl, which ringis substituted at the C(7)′ position with at least the substituent—C≡C—R′, where R′ is H, Si(CH₃)₃, t-butyl, isopropyl, methyl, orcyclopropyl; R₁ and R₁′ are independently one of H, CH₃, CF₃, CH₂CF₃,CH₂CH₃, or cyclopropyl; and R₂ and R₂′ are independently a substitutedor unsubstituted at least partially unsaturated 5 or 6 membered cyclicor heterocyclic ring, wherein if substituted the substituent is one ormore of F, Cl, Br, or NO₂ at the 2′-position. Preferred compoundsaccording to formula XII include:

A still further aspect of the present invention provides a compound ofthe formula XIII, or a salt or prodrug thereof,

wherein Y and Z are taken together with the two intervening carbon atomsto form a ring selected from phenyl and thienyl, which ring issubstituted at the C(7) position with at least the substituent —C≡C—R,where R is H, Si(CH₃)₃, t-butyl, isopropyl, methyl, or cyclopropyl; Y′and Z′ are taken together with the two intervening carbon atoms to forma ring selected from phenyl and thienyl, which ring is substituted atthe C(7)′ position with at least the substituent —C≡C—R′, where R′ is H,Si(CH₃)₃, t-butyl, isopropyl, methyl, or cyclopropyl; R₁ and R₁′ areindependently one of H, CH₃, CF₃, CH₂CH₃, CH₂CF₃, or cyclopropyl; R₂ andR₂′ are independently a substituted or unsubstituted at least partiallyunsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein ifsubstituted the substituent is one or more of F, Cl, Br, or NO₂ at the2′-position; and B is O or NH and wherein —BCH₂B— is optionally replacedwith —N(R₇)—N(R₇)—, where R₇ is one of H, CH₃, alkyl, or cycloalkyl.Preferred compounds according to formula XIII include:

Yet another aspect of the present invention provides a compound of theformula XIV, or a salt or prodrug thereof,

wherein Y and Z are taken together with the two intervening carbon atomsto form a ring selected from phenyl and thienyl, which ring issubstituted at the C(7) position with at least the substituent —C≡C—R,where R is H, Si(CH₃)₃, t-butyl, isopropyl, methyl, or cyclopropyl; Y′and Z′ are taken together with the two intervening carbon atoms to forma ring selected from phenyl and thienyl, which ring is substituted atthe C(7)′ position with at least the substituent —C≡C—R′, where R′ is H,Si(CH₃)₃, t-butyl, isopropyl, methyl, or cyclopropyl; R₁ and R₁′ areindependently one of H, CH₃, CF₃, CH₂CH₃, CH₂CF₃, or cyclopropyl; R₂ andR₂′ are independently a substituted or unsubstituted at least partiallyunsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein ifsubstituted the substituent is one or more of F, Cl, Br, or NO₂ at the2′-position; and B is O, NH, or —N(R₇)—N(R₇)—, where R₇ is one of H,CH₃, alkyl, or cycloalkyl. Preferred compounds according to formula XIVinclude:

Another compound (XV) of the present invention is

n=1, n=2; R=H, SiMe₃, tBu, CH₃,

Ar=phenyl, 2′-flurophenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-pyridylN—O; X=N or CH

Yet another compound (XVI) of the present invention is:

R=H, SiMe₃, tBu, CH₃,

Ar=phenyl, 2′-flurophenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-pyridylN—O; X=N or CH

Still another compound (XVII) of the present invention is:

R=H, SiMe₃, tBu, CH₃,

Ar=phenyl, 2′-flurophenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-pyridylN—O; Y=O, S, NHCH₃

Another compound (XVIII) of the present invention is:

n=0, n=1; R=H, SiMe₃, tBu, CH₃,

Ar=phenyl, 2′-flurophenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-pyridylN—O; Y=O, S, NHCH₃

Yet another compound (XIX) of the present invention is:

R=H, SiMe₃, tBu, CH₃,

Ar=phenyl, 2′-flurophenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-pyridylN—O; Y=O, S, NHCH₃

Still another compound (XX) of the present invention is:

R=H, SiMe₃, tBu, CH₃,

Ar=phenyl, 2′-flurophenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-pyridylN—O; Y=O, S, NHCH₃

A further compound (XXI) of the present invention is:

R=H, SiMe₃, tBu, CH₃,

Ar=phenyl, 2′-flurophenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-pyridylN—O; Y=O, S, NHCH₃

Compounds (XV) to (XXI) above can also have R as CF₃, CCl₃, or CBr₃.

A still further aspect of the present invention provides compositionscomprising compounds of the above kind in a pharmaceutically acceptablecarrier. Such pharmaceutically acceptable carriers are well known in theart.

Another aspect of the invention provides a method for the treatmentand/or prevention of anxiety which comprises administering to a patientin need of such treatment an effective amount of a compound of the abovekinds, or a pharmaceutically acceptable salt thereof or a prodrugthereof.

In the above embodiments by “alkyl” we mean a straight or branchedhalogenated or unhalogenated alkyl group having 1-6 carbon atoms. By“cycloalkyl” we mean one containing 3-7 carbon atoms. Also, in the aboveembodiments by “cyclic” we prefer a phenyl group and by “heterocyclic”we prefer a 2-pyridine or a 2- or 3-thiophene.

The compounds of the present invention are GABA_(A) receptor ligandswhich exhibit anxiolytic activity due to increased agonist efficacy atGABA_(A)/α2, GABA_(A)/α3 and/or GABA_(A)/α5 receptors. The compounds inaccordance with this invention may possess at least 2-fold, suitably atleast 5-fold, and advantageously at least a 10-fold, selective efficacyfor the GABA_(A)/α2, GABA_(A)/α3, and/or GABA_(A)/α5 receptors relativeto the GABA_(A)/α1 receptors. However, compounds which are not selectivein terms of their agonist efficacy for the GABA_(A)/α2, GABA_(A)/α3,and/or GABA_(A)/α5 receptors are also encompassed within the scope ofthe present invention. Such compounds will desirably exhibit functionalselectivity by demonstrating anxiolytic activity with decreasedsedative-hypnotic/muscle relaxant/ataxic activity due to decreasedefficacy at GABA_(A)/α1 receptors.

For use in medicine, the salts of the compounds of formulas (I)-(XXI)will be pharmaceutically acceptable salts. Other salts may, however, beuseful in the preparation of the compounds according to the invention orof their pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example, be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid,acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid,carbonic acid or phosphoric acid. Furthermore, where the compounds ofthe invention carry an acidic moiety, suitable pharmaceuticallyacceptable salts thereof may include alkali metal salts, e.g. sodium orpotassium salts, alkaline earth metal salts, e.g. calcium or magnesiumsalts; and salts formed with suitable organic ligands, e.g. quaternaryammonium salts.

The present invention includes within its scope prodrugs of thecompounds of formulas (I)-(XXI) above. In general, such prodrugs will befunctional derivatives of the compounds of formulas (I)-(XXI) which arereadily convertible in vivo into the required compound of formulas(I)-(XXI). Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in Design ofProdrugs, ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to the invention have at least oneasymmetric center, they may accordingly exist as enantiomers. Where thecompounds according the invention possess two or more asymmetriccenters, they may additionally exist as diastereoisomers. It is to beunderstood that all such isomers and mixtures thereof in any proportionare encompassed within the scope of the present invention.

The compounds according to the present invention exhibit anxiolyticactivity, as may be demonstrated in rats by a positive response in apreclinical test for anti-anxiety efficacy (e.g., situational anxiety ordefensive withdrawal). Moreover, the compounds of the invention aresubstantially non-sedating and non-ataxic as may be confirmed by anappropriate result obtained from the locomotor activity test and rotorodparadigm, respectively.

The compounds according to the present invention may also exhibitanticonvulsant activity. This can be demonstrated by the ability toblock pentylenetetrazole-induced seizures in rodents.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, metered aerosolor liquid sprays, drops, ampoules, auto-injector devices orsuppositories; for oral, parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation. Itis also envisioned that the compounds of the present invention may beincorporated into transdermal patches designed to deliver theappropriate amount of the drug in a continuous fashion. For preparingsolid compositions such as tablets, the principal active ingredient ismixed with a pharmaceutical carrier, e.g. conventional tabletingingredients such as corn starch, lactose, sucrose, sorbitol, talc,stearic acid, magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture for a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be easily subdivided intoequally effective unit dosage forms such as tablets, pills and capsules.This solid performulation composition is then subdivided into unitdosage forms of the type described above containing from 0.1 to about500 mg of the active ingredient of the present invention. Typical unitdosage forms contain from 1 to 100 mg, for example, 1, 2, 5, 10, 25, 50or 100 mg, of the active ingredient. The tablets or pills of the novelcomposition can be coated or otherwise compounded to provide a dosagefrom affording the advantage of prolonged action. For example, thetablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which, serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterials can be used for such enteric layers or coatings, suchmaterials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone or gelatin.

In the treatment of anxiety, suitable dosage level is about 0.01 to 250mg/kg per day, preferably about 0.05 to 100 mg/kg per day, andespecially about 0.05 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day, or on a continuousbasis via, for example, the use of a transdermal patch.

DETAILED DESCRIPTION OF THE INVENTION

The bromide 1 available from reference ¹ was reacted withtrimethylsilyacetylene in the presence of a palladium catalyst toprovide trimethylsilyl analog 2.^(4,5,6) This product was methylatedwith methyl iodide/sodium hydride to give the N-methyl benzodiazepine 3.This was subjected to fluoride-mediated desilation to furnish 4(QHII-066).

Procedure for QHII-066

7-Trimethylsilylacetyleno-5-phenyl-1,3-dihydrobenzo[e]-1,4-diazepin-2-one2.^(4,5,8)

A mixture of 1¹ (1 g, 3.17 mmole available from reference 1) in triethylamine (30 mL) and CH₃CN (20 mL) with trimethylsilylacetylene (622.7 mg,6.34 mmole) and bis(tri-phenylphosphine)-palladium (II) acetate (118 mg,0.16 mmol) was heated to reflux under nitrogen. After 12 hours, thereaction mixture was cooled to room temperature and filtered. Thefiltrate was concentrated in vacuum and the residue was treated with asaturated aqueous solution of NaHCO₃ (30 mL), and extracted with CH₂Cl₂(3×50 mL). The organic layers were combined and washed with brine anddried (Na₂SO₄). After removal of solvent under reduced pressure, theresidue was purified via flash chromatography (silica gel,EtOAc/hexanes:1/1) to furnish 3 as a yellow powder (791 mg, 75%): mp:190-191.5° C.; IR (KBr) 3011, 2281, 1686, 1610, 1486, 1325, 1249, 839,700 cm⁻¹; 1H NMR (CDCl₃) δ 0.21 (s, 9H), 4.31 (s, 2H), 7.09 (d, 1H,J=8.25 Hz), 7.21-7.61 (br, 7H), 10.17 (s, 1H); MS (CI) m/e (relativeintensity) 333 (M⁺+1, 100). This material was used in the next step.

1-Methyl-7-trimethylsilylacetyleno-5-phenyl-1,3-dihydrobenzo[e]-1,4-diazepin-2-one3.⁷

A mixture of 2 (485 mg, 1.46 mmol) was dissolved in dry THF (20 mL) at0° C. and NaH (60% in mineral oil, 70 mg, 1.75 mmol) was added to thesolution in one portion. The slurry was then stirred for 20 min at 0° C.and CH₃I (311 mg, 2.19 mmol) was added to the mixture and it was warmedup to room temperature. After the mixture stirred for 3 hours at roomtemperature, the THF was then removed under reduced pressure. Theresidue was purified by flash chromatography [hexanes/EtOAc (1:4)] toprovide the title compound 3 (303 mg, 60%) as a white solid: mp:177-178° C.; IR (KBr) 2954, 2147, 1687, 1612, 1491, 1382, 1115, 1075,839, 700 cm⁻¹; 1HNMR (CDCl₃) δ(ppm), 3.18 (s, 3H), 3.54 (d, 1H, J=10.8Hz), 4.60 (d, 1H, J=10.8 Hz), 7.05 (s, 1H), 7.07 (d, 1H, J=8.58 Hz),7.20-7.27 (m, 3H), 7.37-7.42 (m, 3H); MS (EI) m/e 346 (M⁺, 90), 318(100), 303(19), 165(22), 151(20). Anal. Calcd. for C₂₁H₂₂N₂OSi: C,72.79; H, 6.40; N, 8.08. Found: C, 72.50; H, 6.68; N, 8.04.

1-Methyl-7-acetyleno-5-phenyl-1,3-dihydro-benzo[e]-1,4-diazepin-2-one 4(QHII-066).⁷

A solution of 3 (100 mg,) in THF (30 mL) was treated withtetrabutylammonium fluoride (1M in THF). The mixture was stirred for 20minutes at room temperature before water (30 mL) was added. The mixturewas then extracted with EtOAc (3×30 mL). The combined organic extractswere washed with brine and dried (Na₂SO₄). The solvent was removed undervacuum and the residue which resulted was passed through a wash column(silica gel, EtOAc/hexanes:4/1) to give 4 (QHII-066) as light yellowcrystals (71 mg, 90%): mp: 163-165° C.; IR (KBr) 2965, 1680, 1605, 1387,1121, 833, 747 cm⁻¹; ¹HNMR (CDCl₃) δ (ppm) 3.38 (s, 3H), 3.75 (d, 1H,J=10.8 Hz), 4.80 (d, 1H, J=10.9 Hz), 5.28 (s, 1H), 7.29 (d, 1H, J=8.5Hz), 7.35-7.45 (m, 4H), 7.55-7.59 (m, 2H), 7.62 (dd, 1H, J=8.5 Hz, 2.0Hz); MS (EI) m/e (relative intensity) 274 (M⁺, 100), 259 (12), 246(100), 189 (12).122(19), 105 (42). Anal. Calcd. for C₁₈H₁₄N₂O.⅔H₂O,Calculated: C, 75.51; H, 4.89; N, 9.78. Found: C, 75.59; H, 5.17; N,9.62.

The bromide 1 was reacted with diethylphosphorochloridate in thepresence of sodium hydride, followed by addition of ethylisocyanoacetate to provide the ester 5. This was converted to thetrimethylsilylacetyleno compound 6 (XLiXHeII-048) under standardconditions (Pd-mediated, Heck-type coupling).⁸ Treatment of 6 withfluoride gave the title compound 7 (XHell-053).

Procedure for XHe-II-053

Ethyl8-bromo-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate5.

This benzodiazepine 5 was obtained in 45% yield from 1¹ analogous to theliterature procedure² as a white solid. 2: mp: 174-175° C.; IR (KBr)2978, 1712, 1609, 1491 cm⁻¹; ¹H NMR (CDCl₃) δ 1.44 (t, 3H, J=7.1 Hz),4.09 (d, 1H, J=12.1 Hz), 4.38-4.49 (m, 2H), 6.08 (d, 1H, J=12.3 Hz),7.40-7.53 (m, 6H), 7.60 (d, 1H, J=2.2 Hz), 7.82 (dd, 1H, J=8.6 Hz and2.2 Hz), 7.95 (s, 1H); MS (EI) m/e (relative intensity) 411 (34), 410(M⁺, 8), 409 (34), 365 (61), 363 (61), 337 (100), 335 (100), 285 (21),232, (17). Anal. Calcd. for C₂₀H₁₆BrN₃O₂: C, 58.55; H, 3.93; N, 10.24.Found: C, 58.30, H, 3.91; N, 9.90.

Ethyl8-trimethylsilylacetylenyl-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate6 (XLiXHeII-048).^(4,5,8)

A mixture of bromide 5 (0.3 g, 0.73 mmol), trimethylsilylacetylene(0.143 g, 1.46 mmol) and bis(triphenylphosphine)-palladium-(I) acetate(55 mg, 0.073 mmol) in a mixed solvent system of toluene (20 mL) andanhydrous TEA (50 mL) was heated to reflux under argon. After stirringfor 12 hours at reflux, the mixture was cooled to room temperature andthe precipitate which formed was removed by filtration. The filtrate wasconcentrated under reduced pressure and the residue was treated with asaturated aqueous solution of NaHCO₃ (20 mL), and extracted with CHCl₃(3×25 mL). The combined extracts were washed with brine and dried(Na₂SO₄). After removal of solvent under reduced pressure, the residuewas purified by flash chromatography (silica gel, EtOAc) to afford 6(XLiXHeII-048) as a white solid (0.29 g, 93%). This benzodiazepine canalso be obtained from 2 in 45% yield by following the same procedure 6(XLiXHeII-048): mp: 170-172° C.; IR (KBr) 2958, 2152, 1718 cm⁻¹; ¹H NMR(CDCl₃) δ 0.23 (s, 9H), 1.42 (t, 3H, J=7.2 Hz), 4.04 (d, 1H, J=12.6 Hz),4.41 (m, 2H, J=7.2 Hz), 6.23 (d, 1H, J=12.6 Hz), 7.35-7.55 (m, 7H), 7.73(dd, 1H, J=8.3 Hz, J=1.9 Hz), 7.93 (s, 1H); MS (EI) m/e (relativeintensity) 427 (M⁺, 76), 412 (5), 381 (55), 353 (100) 303 (10), 287 (7).Anal. Calcd. for C₂₅H₂₅N₃O₂Si.⅓ EtOAc: C, 69.22; H, 6.01; N, 9.20.Found: C, 68.87; H, 5.81; N, 9.37.

Ethyl8-acetylenyl-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate7 (XHeII-053).⁷

A solution of 6 (XLiXHeII-048) (0.17 g, 0.41 mmol), in THF (15 mL) wastreated with Bu₄NF.H₂O (0.16 g, 0.62 mmol). The mixture which resultedwas allowed to stir for 30 min at room temperature after which themixture was added to H₂O (10 mL) and extracted with EtOAc (3×25 mL). Thecombined organic extracts were washed with brine (25 mL) and dried(Na₂SO₄). After removal of solvent under reduced pressure, the residuewas purified by a wash column (silica gel, EtOAc) to furnish 7(XHeII-053) (0.12 g, 85%) as a white solid: mp 237-239° C.; IR (KBr)3159, 3107, 2092, 1721, 1606 cm⁻¹; ¹H NMR (CDCl₃) δ 1.44 (t, 3H, J=7.1Hz), 3.20 (s, 1H), 4.13 (d, 1H, J=10.22 Hz), 4.41-4.48 (m, 2H), 6.11 (d,1H, J=12 Hz), 7.42-7.63 (m, 7H), 7.81 (dd, 1H, J=8.3 Hz and 1.8 Hz),8.03 (s, 1H); MS (EI) m/e (relative intensity) 355 (M⁺, 83), 309 (70),281 (100), 253 (12), 231 (18), 178 (20). Anal. Calcd. forC₂₂H₁₇N₃O₂.¾H₂O: C, 71.63; H, 5.05; N, 11.39. Found: C, 71.27; H, 4.71;N, 11.03.

The bromide 1, available from reference 1, was stirred with thedi-4-morpholino-phosphinic chloride, followed by addition ofacetylhydrazide to furnish triazolo-benzodiazepine 8. This material 8was subjected to a Heck-type coupling reaction (TMS-C≡CH,Pd-mediated)^(4,7,8) to furnish ligand 9. This analog was converted into10 (XLi270) on stirring with fluoride anion as shown in Scheme 3.

Procedure for XLi 270

8-Bromo-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine 8.³

A solution of 1¹ (1 g, 3.07 mmol of7-bromo-5-phenyl-1,4-benzodiazepine-2-one) in dry THF (20 mL) was cooledin an ice-water bath and a 60% dispersion of sodium hydride (152.2 mg)was added in one portion. After 20 minutes, di-4-morpholinylphosphinicchloride³ (943.9 mg, 4.76 mmol) was added at 0° C. and this was stirredfor 30 minutes and allowed to warm to room temperature. The mixture wasstirred for 1.5 hours. To this mixture was then added a solution ofacetylhydrazide (521.9 mg, 7.14 mmol) in dry butanol (5 mL) and stirringwas continued at room temperature for 10 min. The solvents wereevaporated and the residue was dissolved in butanol (10 mL) and heatedto reflux for 5 hours. Butanol was removed under reduced pressure andthe residue was partitioned between CH₂Cl₂ (50 mL) and water (50 mL).The water layer was extracted by CH₂Cl₂ (3×30 mL). The combined organiclayer was washed by brine (30 mL). The organic layer was dried (Na₂SO₄)and the solvent was removed under vacuum. The residue was purified byflash chromatography (silica gel) to provide pure 8 [539.5 mg (40%yield)] as a white solid: mp 268.5-270° C.; IR (KBr) 2358, 1607, 1538,1484, 1311, 1000, 801, 697 cm⁻¹; ¹H NMR (CDCl₃) δ 2.82(s, 3H), 4.11(d,1H, J=12.8 Hz), 5.49 (d, 1H, J=12.8 Hz), 7.21-7.68(m, 7H), 7.75 (dd, 1H,J=0.58 Hz, J=1.5 Hz); MS (EI) m/e (relative intensity) 354 (34), (M⁺,16), 352 (34), 325(33), 323 (34), 273 (63), 245 (31), 232 (19), 204(100), 183(23), 177 (36), 151 (24). Anal. Calcd. for C₁₇H₁₃BrN₄: C,57.81; H, 3.71; N, 15.86. Found C, 57.57; H, 3.64: N, 15.70.

8-Trimethylsilylacetylenyl-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepine9.^(4,5,8) (XLi269).

A mixture of 8(8-bromo-1-methyl-6-phenyl-4-H-s-triazolo-[4,3-a][1,4]benzodiazepine,300 mg, 0.85 mmol), trimethylsilylacetylene (208.5 mg, 2.12 mmol) andbis(triphenylphosphine)-palladium(II) acetate in a mixed solvent systemof EtN₃ (5 mL) and CH₃CN (8 mL) was heated to reflux under nitrogen.After stirring for 6 hours at reflux. The mixture was cooled to roomtemperature. The mixture was concentrated under reduced pressure and H₂O(30 mL) was added. The mixture was extracted with CH₂Cl₂ (3×50 mL). Thecombined extracts were washed with brine and dried (Na₂SO₄). Afterremoval of solvent under reduced pressure, the residue was purified byflash chromatography (silica gel, EtOH/EtOAc) to afford benzodiazepine 9(185 mg, 60% yield) as a white solid: mp 229-233° C.; IR (KBr) 2957,2156, 1609, 1537, 1491, 1424, 1315, 1249, 881, 844, 750 cm⁻¹; ¹H NMR(CDCl₃) δ 0.23 (s, 9H), 2.68 (s, 3H), 4.11 (d, 1H, J=12.5 Hz), 5.49 (d,1H, J=13.0 Hz), 7.21-7.68(m, 7H), 7.75(dd, 1H, J=8.5 Hz, J=1.5 Hz); MS(EI) m/e (relative intensity) 370 (M⁺, 80), 355 (44), 341 (60), 286(34), 177 (51), 163 (52) 143 (100), 129 (19), 115 (28). Anal. Calcd. forC₂₂H₂₂N₄Si: C, 71.31; H, 5.98; N, 15.12. Found: C, 70.90; H, 5.93; N,15.08.

8-Acetylenyl-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine10 (Xli-270).⁷

A solution of 9[trimethylsilylacetylenyl-1-methyl-6-phenyl-4H-s-triazolo-[4,3-a]-[1,4]-benzodiazepine(106.4 mg, 0.288 mmol)] in dry THF (20 mL) was treated with Bu₄NF (1.0 Min THF, 112.8 mg, 0.431 mmol). The mixture which resulted was allowed tostir for 5 min at room temperature after which the mixture was added toH₂O (10 mL) and extracted with CH₂Cl₂ (3×25 mL). The combined organicextracts were washed with brine (25 mL) and dried (Na₂SO₄). Afterremoval of solvent under reduced pressure, the residue was crystallizedfrom EtOAc to provide benzodiazepine 10 (XLi270) (66.8 mg, 80% yield) asa white solid: mp>250° C. (dec); IR (KBr) 3198, 2158, 1609, 1538, 1491,1425, 1317, 1002, 838, 748, 695 cm⁻¹; ¹H NMR (CDCl₃) δ 2.78 (s, 3H),3.15 (s, 1H), 4.11 (d, 2H, J=12.8 Hz), 5.91 (d, 1H, J=12.8 Hz),7.35-7.85 (m, 8H); MS (EI) (relative intensity) 298 (M⁺, 100), 269 (78),230 (48), 228 (65), 201 (20), 127 (65), 115 (42), 101 (54). Anal. Calcd.for C₁₉H₁₄N₄.½CH₃OH: C, 74.50; H, 5.13; N, 17.82. Found: C, 74.33; H,4.83; N, 17.77,

The 7-bromo-2′-fluorobenzodiazepine 12 (available from reference 1) wasreacted with sodium hydride and diethylphosphorochloridate and this wasfollowed by addition of ethyl isocyanoacetate to provide benzimidazointermediate 13 (JYI-032),² as illustrated in Scheme 4. This materialwas heated with trimethysilylacetylene in a Heck-type coupling reaction⁸to provide the trimethylsilyl analog 14 (JYI-038). The silyl group wasremoved from 14 on treatment with fluoride anion to furnish 15, a2′-fluoro analog of XHeII-053, in excellent yield.

Procedure:

Ethyl8-bromo-6-(2′-fluorophenyl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate13 (JYI-032).

A solution of 121 (7.0 g, 21.0 mmol) in THF (50 mL) was cooled inice-water, and sodium hydride (1.0 g, 25.2 mmol) was added in oneportion. After 30 min, diethyl phosphorochloridate (5.62 g, 31.5 mmol)was added dropwise, and the solution which resulted was stirredcontinuously for 30 min with cooling from an ice bath. A solution ofethyl isocyanoacetate (4.22 g, 25.2 mmol) and sodium hydride (1.17 g,29.4 mmol) in THF (10 mL), which had stirred for 30 min with ice-bathcooling, was added slowly via a cannula. After stirring for another 30min with cooling, the reaction mixture was allowed to stir at roomtemperature overnight. The mixture was then added to H₂O (10 mL) andextracted with EtOAc (3×50 mL). The combined organic extracts werewashed with brine (2×50 mL) and dried (Na₂SO₄). The solvent wasevaporated under reduced pressure and the residue was purified by flashchromatography (silica gel, hexanes/EtOAc:2/1) to afford 13 (JYI-032,5.2 g, 58%) as a white solid: mp 200-201.5° C.; IR (KBr) 2977, 1718,1610, 1491, 1450 cm⁻¹; ¹H NMR (DMSO-d₆) δ 1.30 (t, 3H, J=4.2 Hz), 4.28(bs, 1H), 4.30 (q, 2H, J=4.2 Hz), 5.75 (bs, 1H), 7.20 (t, 1H, J=5.6 Hz),7.30 (t, 1H, J=4.5 Hz), 7.40 (s, 1H), 7.54 (m, 2H), 7.85 (d, 1H, J=5.2Hz), 7.96 (dd, 1H, J=5.2 Hz and 1.3 Hz), 8.44 (s, 1H); MS (EI) m/e(relative intensity) 428 (7), 381 (58), 355 (100), 303 (37), 274 (36),247 (35), 234 (52), 154 (71), 127 (62). Anal Calcd. for C₂₀H₁₅N₃O₂FBr:C, 56.09; H, 3.53; N, 9.81. Found: C, 56.02; H, 3.51; N, 9.58.

Ethyl8-trimethylsilylacetylenyl-6-(2′-fluorophenyl)-4H-benzo[f]-imidazo[1,5-α][1,4]diazepine-3-carboxylate14 (JYI-038).

A mixture of bromide 13 (JYI-032, 1.40 g, 3.3 mmol),trimethylsilylacetylene (0.65 g, 6.6 mmol) andbis(triphenylphosphine)-palladium (II) acetate (0.25 g, 0.33 mmol) in amixed solvent system of CH₃CN (80 mL) and anhydrous triethylamine (50mL) was heated to reflux under argon. After stirring for 2 h at reflux,the mixture was cooled to room temperature and the precipitate whichformed was removed by filtration. The filtrate was concentrated underreduced pressure and the residue was treated with a saturated aqueoussolution of NaHCO₃ (40 mL), and extracted with CHCl₃ (3×50 mL). Thecombined organic extracts were washed with brine (2×20 mL) and dried(Na₂SO₄). After removal of solvent under reduced pressure, the residuewas purified by flash chromatography (silica gel, hexanes/EtOAc:3/1) toafford 14 (JYI-038, 1.2 g, 82%) as a white solid: mp 196-197.5° C.; IR(KBr) 2959, 2157, 1709, 1613, 1494, 1451, 1252 cm⁻¹; ¹H NMR (DMSO-d₆) δ0.20 (s, 9H), 1.32 (t, 3H, J=7.1 Hz), 4.18 (bs, 1H), 4.32 (q, 2H, J=7.1Hz), 5.78 (bs, 1H), 7.25 (t, 1H, J=11.5 Hz), 7.30-7.35 (m, 4H), 7.81 (d,1H, J=6.6 Hz), 7.93 (d, 1H, J=8.4 Hz), 8.49 (s, 1H); MS (EI) m/e(relative intensity) 445 (37), 399 (51), 371 (100), 235 (71), 192 (66),178 (75). Anal. Calcd. for C₂₅H₂₄N₃O₂FSi: C, 67.39; H, 5.42; N, 9.43.Found: C, 66.98; H, 5.46; N, 9.19.

8-Acetyleno-6-(2′-fluorophenyl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate15 (JY-XHE-053).

A solution of 14 (JYI-038, 80 mg, 0.18 mmol) in THF (5 mL) was treatedwith Bu₄NF (0.5 mL, 1.0M solution in THF). The mixture which resultedwas allowed to stir for 5 min at room temperature after which themixture was added to H₂O (5 mL) and extracted with EtOAc (3×10 mL). Thecombined organic extracts were washed with brine (2×10 mL) and dried(Na₂SO₄). The solvent was removed under reduced pressure and the residuewas purified by flash chromatography (silica gel, EtOAc) to afford 15(JY-XHE-053, 67 mg, 80%) as a white solid: mp 223.5-224.5° C.; IR (KBr)3288, 2979, 1712, 1621, 1491, 1255, 1190 cm⁻¹; ¹H NMR (DMSO-d₆) δ 1.34(t, 3H, J=7.1 Hz), 4.27 (bs, 1H), 4.36 (q, 2H, J=7.1 Hz), 4.47 (s, 1H),5.80 (bs, 1H), 7.22 (t, 1H, J=8.4 Hz), 7.30-7.60 (m, 4H), 7.85 (d, 1H,J=6.6 Hz), 7.92 (d, 1H, J=8.4 Hz), 8.83 (s, 1H); MS (EI) m/e (relativeintensity) 373 (28), 327 (47), 299 (100), 249(22), 178 (50).

Anal. Calcd. for C₂₂H₁₆N₃O₂F.½H₂O: C, 69.10; H, 4.48; N, 10.99. Found:C, 69.19; H, 4.39; N, 10.68.

The 7-bromo-2′-fluorobenzodiazepine 12 was stirred with sodium hydrideand di-4-morpholinylphosphinic chloride, followed by addition of acetichydrazide, according to the published procedure³ to providetriazolobenzodiazepine 16 (JYI-73), as illustrated in Scheme 5. Thiscompound 16 underwent the palladium-mediated Heck-type couplingreactions with trimethylsilylacetylene to furnish the 8-trimethylsilylsubstituted analog 17 (JYI-72). Removal of the silyl group from 17furnished the 8-acetyleno triazolobenzodiazepine 18 (JYI-70).

Procedure:

8-Bromo-1-methyl-6-(2′-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine16 (JYI-73).

A solution of 12 (JYI-032, 7.0 g, 21.0 mmol) in THF (50 mL) was cooledin ice-water, and sodium hydride (0.72 g, 18 mmol) was added in oneportion. After 1 hour, di-4-morpholinylphosphinic chloride (4.84 g, 22.5mmol) was added, and the solution which resulted was stirredcontinuously for 2 hours at room temperature. To this mixture was thenadded a solution of acetic hydrazide (2.47 g, 30 mmol) in n-BuOH (20 mL)and stirring was continued at room temperature for 15 min. The solventswere evaporated and the residue was dissolved in n-BuOH (25 mL) andheated to reflux for 2 hours. n-Butanol was evaporated and the residuewas partitioned between CH₂Cl₂ and brine. The CH₂Cl₂ layer was dried andremoved under reduced pressure after which the residue was purified byflash chromatography (silica gel, EtOAc) to afford 16 (JYI-73, 2.2 g,40%) as a white solid: mp 213-214° C.; IR (KBr) 1610, 1484, 1426, 1314cm⁻¹; ¹H NMR (DMSO-d₆) δ 2.56 (s, 3H), 4.28 (d, 1H, J=12.9 Hz), 5.26 (d,1H, J=12.9 Hz), 7.24 (t, 1H, J=8.3 Hz), 7.29 (t, 1H, J=7.2 Hz), 7.35 (s,1H), 7.43-7.60 (m, 2H), 7.83 (d, 1H, J=8.7 Hz), 7.98 (dd, 1H, J=8.7 Hzand 2.3 Hz); MS (EI) m/e (relative intensity) 371 (5), 341 (34), 222(100), 195 (19), 181 (28), 111 (72). Anal. Calcd. for C₁₇H₁₂N₄FBr: C,55.01; H, 3.26; N, 15.09. Found: C, 54.76; H, 3.29; N, 14.74.

8-Trimethylsilylacetylenyl-1-methyl-6-(2′-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine17 (JYI-72).

A mixture of bromide 16 (JYI-73, 1.40 g, 3.8 mmol),trimethylsilylacetylene (0.65 g, 6.6 mmol) andbis(triphenylphosphine)palladium (II) acetate (0.25 g, 0.33 mmol) in amixed solvent system of CH₃CN (80 mL) and anhydrous triethylamine (50mL) was heated to reflux under argon. After stirring for 2 hours atreflux, the mixture was cooled to room temperature and the precipitatewhich formed was removed by filtration. The filtrate was concentratedunder reduced pressure and the residue was treated with a saturatedaqueous solution of NaHCO₃ (40 mL), and extracted with CHCl₃ (3×50 mL).The combined organic extracts were washed with brine (2×10 mL) and dried(Na₂SO₄). After removal of solvent under reduced pressure, the residuewas purified by flash chromatography (silica gel, EtOAc) to afford 17(JYI-72, 1.15 g, 77%) as a gray solid: mp 218-219° C.; IR (KBr) 2958,2157, 1612, 1537, 1493, 1452, 1317, 1249 cm⁻¹; ¹H NMR (DMSO-d₆) δ 0.21(s, 9H), 2.56 (s, 3H), 4.23 (s, 1H, J=12.9 Hz), 7.26 (t, 1H, J=8.4 Hz),7.29-7.83 (m, 6H); MS (EI) m/e (relative intensity) 388 (65), 373 (14),359 (77), 304 (44), 152 (100). Anal. Calcd. for C₂₂H₂₁N₄SiF.0.7H₂O: C,65.87; H, 5.62; N, 13.94. Found: C, 65.88; H, 5.34; N, 13.94.

8-Acetyleno-1-methyl-6-(2′-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine18 (JYI-70).

A solution of 17 (JYI-72, 2.0 g, 5 mmol) in THF (20 mL) was treated withBu₄NF (4 mL, 1.0M solution in THF). The mixture which resulted wasallowed to stir for 5 min at room temperature after which the mixturewas added to H₂O (20 mL) and extracted with CH₂Cl₂ (3×50 mL). Thecombined organic extracts were washed with brine (2×15 mL) and dried(Na₂SO₄). After removal of solvent under reduced pressure, the residuewas purified by flash chromatography (silica gel, EtOAc/MeOH:100/1) toafford 18 (JYI-70, 1.1 g, 70%) as a pale yellow solid: mp>250° C. (dec);IR (KBr) 3205, 1612, 1493, 1426, 1317 cm⁻¹; ¹H NMR (DMSO-d₆) δ 2.54 (s,3H), 4.22 (d, 1H, J=12.9 Hz), 4.39 (s, 1H), 5.26 (d, 1H, J=12.9 Hz),7.22 (t, 1H, J=8.3 Hz), 7.32-7.55 (m, 4H), 7.97 (m, 2H); MS (EI) m/e(relative intensity) 316 (72), 287 (100), 246 (69), 153 (16), 127 (62).Anal. Calcd. for C₁₉H₁₃N₄F.0.6 CH₃OH: C, 70.16; H, 4.37; N, 16.55.Found: C, 69.98; H, 4.31; N, 16.70.

2-Amino-5-bromo-2′-chlorobenzophenone 19 was obtained from simplestarting materials, 4-bromoaniline and 2-chlorobenzoyl chloride,according to the improved conditions in the literature.⁹ Thebenzodiazepine 20, available from reference 1, was stirred with sodiumhydride and di-4-morpholinophosphinic chloride, followed by addition ofacetylhydrazide to furnish triazolobenzodiazepine 21 (dm-II-90).³ Theligand 22 (XLi-JY-DMH-TMS) was obtained by a Heck coupling reaction of21 (dm-II-90) with trimethylsilylacetylene.^(4,7,8) This compound wasconverted into acetylene 23 (XLi-JY-DMH)⁷ on stirring with fluorideanion as shown in Scheme 6.

2-Amino-5-bromo-2′-chlorobenzophenone 19⁹

2-Chlorobenzoyl chloride (177 mL, 1.4 mol) was cooled in a 2-L flaskequipped with a condenser and a thermometer to 0° C. with an ice-waterbath and 4-bromoaniline (100 g, 0.58 mol) was added to the cooledsolution. The mixture was heated to 120° C. and kept at this temperaturefor 1 h until analysis by TLC indicated 4-bromoaniline had been consumed(EtOAc:hexane, 1:4). The solution was heated to 160° C. and anhydrousZnCl₂ (95 g, 0.70 mol, flamed dried) was added in one portion. Thetemperature was increased to 195° C. and stirring was maintained at thistemperature for 3 hr until no more bubbles were evolved. The mixture wascooled to 120° C. and aq HCl (12%, 350 mL) was added dropwise slowly.The mixture was kept at reflux for 20 min, after which the aq layer waspoured off. This procedure with aq HCl was repeated 4 times. Water (350mL) was then added, and the mixture held at reflux for 20 min and thenthe water was poured off. This was repeated several times until thesolid was not a block any more. Then H₂SO₄ (72%, 700 mL) was added tothe residue and the mixture was heated to reflux for about 1 hr untilthe reaction mixture became a homogeneous dark colored solution. The hotacidic solution was poured into a mixture of ice and water withstirring. The precipitate which resulted was filtered and washed with alarge amount of cold water until the pH value of the solid was about 6.The solid was then suspended in ice water and aq NaOH (40%, 290 mL) wasadded carefully. The mixture which resulted was stirred for 2 hrs. Thesolid was filtered and washed with ice water. The suspension of thesolid in ice water was adjusted carefully to approximately pH=3 with aqH₂SO₄ (40%) dropwise. The solid which remained was filtered and washedwith water to neutrality. The yellow solid 19 (66.1 g, 37.0%) was driedand used directly in the next step without further purification. ¹H NMR(300 MHz, CDCl₃) δ 6.49 (s, br, 2H), 6.65 (d, 1H, J=8.82 Hz), 7.26-7.8(m, 6H).

8-Bromo-5-(2′-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a]-1,4-benzodiazepine21 (dm-II-90)³

A solution of benzodiazepine 20 (20 g, 57 mmol, available fromreference 1) in dry THF (250 mL) was cooled to −5° C. and a 60%dispersion of sodium hydride (3.66 g, 92 mmol) was added in one portion.The mixture was allowed to warm to rt with stirring and the stirring wascontinued at rt until no more bubbles were evolved. The suspension wascooled to −5° C. after which di-4-morpholinylphosphinic chloride (21.8g, 86 mmol) was added and this mixture was stirred for 30 min andallowed to warm to rt. The mixture was stirred for an additional 1.5 hr.To the mixture was then added a solution of acetylhydrazide (9.42 g, 114mmol) in butanol (60 mL) and stirring was continued at rt for 10 min.The solvent was removed under reduced pressure and the residue was takenup in butanol (100 mL) and held at reflux for 2 hr. Butanol was removedunder reduced pressure and the residue was partitioned between CH₂Cl₂(200 mL) and H₂O (100 mL). The aq layer was extracted 4 times and theorganic layers combined. The organic layer was washed with brine anddried (Na₂SO₄). After the solvent was removed under reduced pressure,the residue was crystallized from EtOAc-Et₂O to provide the puretriazolobenzodiazepine 21 (dm-II-90, 14 g, 63.2%) as a yellow solid: mp265-267° C. [lit 274-275° C.]⁽¹⁰⁾; IR (KBr) 3120 (br.), 1686, 1479,1386, 1014, 827, 747 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 2.42 (s, 1H), 4.18(d, 1H, J=12.9 Hz), 5.56 (d, 1H, J=12.9 Hz), 7.36 (m, 3H), 7.43 (m, 2H),7.61 (m, 1H), 7.80 (dd, 1H, J=2.1 Hz, 8.7 Hz); MS (EI) m/e (relintensity) 386 (M⁺, 45), 357 (100); Anal. Calcd. ForC₁₇H₁₂N₄BrCl.0.5H₂O: C, 51.65; H, 3.32; N, 14.18. Found C, 51.95; H,2.97; N, 13.91.

8-Trimethylsilylacetylenyl-5-(2′-chlorophenyl)-1-methyl-4H-s-triazolo-[4,3-a]-1,4-benzodiazepine22 (XLi-JY-DMH-TMS)^(4,7,8)

A mixture of 21 (7.75 g, 20 mmol), acetonitrile (600 mL), triethylamine(500 mL) and bis(triphenylphosphine)-palladium (II) acetate (1.2 g, 1.6mmol) was degassed. Trimethylsilylacetylene (5.65 mL, 40 mmol) was thenadded and the solution was degassed again. The solution was then heatedto reflux for 4 hr until analysis by TLC indicated the starting materialhad disappeared. The mixture was cooled to rt and concentrated underreduced pressure. The residue was partitioned between H₂O (50 mL) andEtOAc (2×200 mL). The combined organic layer was washed with brine anddried (Na₂SO₄). The residue was purified by flash chromatography onsilica gel (CHCl₃) to furnish the trimethylsilyl analogue 22(XLi-JY-DMH-TMS, 3 g, 37.0%) as white solid: mp 265-267° C.; IR (KBr)2930, 1618, 1554, 1497, 1429, 1316, 885, 847 cm⁻¹; ¹H NMR (300 MHz,CDCl₃) δ 0.24 (s, 9H), 2.65 (s, 3H), 4.15 (d, 1H, J=12.9 Hz), 5.52 (d,1H, J=12.9 Hz), 7.35-7.45 (m, 5H), 7.61 (m, 1H), 7.72 (dd, 1H, J=1.8 Hz,8.4 Hz); MS (EI) m/e (rel intensity) 404 (M⁺, 90), 375 (100); Anal.Calcd. For C₂₂H₂₁N₄SiCl: C, 65.33; H, 5.24; N, 13.86. Found: C, 64.99;H, 4.98; N, 13.79.

8-Acetyleno-5-(2′-chlorophenyl)-1-methyl-4H-s-triazolo-[4,3-a]-1,4-benzodiazepine23 (XLi-JY-DMH)⁷

A solution of benzodiazepine 22 (1.25 g, 31 mmol) in THF (250 mL) wascooled to −30° C. and treated with Bu₄NF.xH₂O (0.97 g, 37 mmol). Afterthe mixture was stirred for 5 min, analysis by TLC (silica gel;EtOAc:EtOH 4:1) indicated starting material had disappeared. Water (70mL) was then added and the mixture was allowed to warm to rt. Themixture was then extracted with EtOAc (2×200 mL). The organic layer waswashed with brine and dried (Na₂SO₄). After removal of the solvent underreduced pressure, the residue was washed successively with ethyl ether,ethyl acetate and chloroform. After drying, the title compound 23(XLi-JY-DMH) was obtained (1.0 g, 97.3%) as a white solid: mp>250° C.(dec); IR (KBr) 3185, 1623, 1543, 1497, 1429, 756 cm⁻¹; ¹H NMR (300 MHz,CDCl₃) δ 2.65 (s, 3H), 3.17 (s, 1H), 4.18 (d, 1H, J=12.9 Hz), 5.54 (d,1H, 12.9 Hz), 7.34(m, 2H), 7.41-7.45 (m, 3H), 7.6 (m, 1H), 7.75 (dd, 1H,J=1.8 Hz, 8.4 Hz); MS (EI) m/e (rel intensity) 332 (M⁺, 78) 303 (100).

Esters 37 (dm-II-30), 38(dm-II-33) and 41 (dm-II-20) were preparedaccording to the general procedure described in item [0067] from thestarting acids and different alcohols, respectively. The bromide 37 wasconverted into the trimethlyacetylenyl compound 39 (dm-II-35) understandard conditions (Pd-mediated, Heck-type coupling)^(4,7,8) (Scheme7).

General Procedure for Preparing the Esters.

The acid was dissolved in DMF (10 mL/mmol S.M.) and CDI (1.2 eq) wasadded. The reaction mixture was stirred at room temperature for 3 hfollowed by addition of the alcohol (10 eq) and DBU (1 eq). The stirringwas maintained until the disappearance of all the starting material asdetermined by TLC (EtOAc:EtOH 4:1). The reaction mixture was thenquenched by adding water. The solid which precipitated was filtered andwashed with ethyl ether. It was purified by flash chromatography (EtOAc)on silica gel or neutral aluminum oxide for ester 38.

Trifluoroethyl8-bromo-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate37 (dm-II-30)

A white solid (69.1%) from acid 27 and 2,2,2-trifluoroethanol: mp202-204° C.; IR (KBr) 3114, 1711, 1608, 1495, 1368, 1288, 1158 cm⁻¹; ¹HNMR (300 MHz, CDCl₃) δ 4.10 (d, 1H, J=12.6 Hz), 4.68 (m, 1H), 4.85 (m,1H), 6.02 (d, 1H, J=12.6 Hz), 7.41-7.54 (m, 6H), 7.62 (d, 1H, J=2.1 Hz),7.83 (dd, 1H, J=2.1 Hz, 8.4 Hz), 7.97 (s, 1H); MS (EI) m/e (relintensity) 463 (M⁺, 14), 465 (14).

Trichloroethyl8-bromo-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate38 (dm-II-33)

A white solid (90.9%) from acid 27 and 2,2,2-trichloroethanol: mp113-116° C.; IR (KBr) 3434, 1728, 1610, 1493, 1270, 1146, 1128 cm⁻¹; ¹HNMR (300 MHz, CDCl₃) δ 4.11 (d, 1H, J=12.6 Hz), 4.91 (d, 1H, J=12.0 Hz),5.19 (d, 1H, J=12.0 Hz), 6.12 (d, 1H, J=12.6 Hz), 7.41-7.54 (m, 6H),7.61 (d, 1H, J=2.1 Hz), 7.83 (dd, 1H, J=2.1 Hz, 8.4 Hz); MS (EI) m/e(rel intensity) 511 (M⁺, 45).

Trifluoroethyl8-trimethylsilylacetylenyl-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate39 (dm-II-35)

A white solid (49.8%): mp 107-110° C.; IR (KBr) 2961, 1734, 1611, 1560,1497, 1251, 1159, 1120, 846 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 0.25 (s,9H), 4.08 (d, 1H, J=12.3 Hz), 4.69 (m, 1H), 4.84 (m, 1H), 5.98 (d, 1H,J=12.3 Hz), 7.39-7.57 (m, 7H), 7.76 (dd, 1H, J=1.8 Hz, 8.4 Hz); MS (EI)m/e (rel intensity) 481 (M⁺, 100).

Trifluoroethyl8-acetylenyl-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diaze-pine-3-carboxylate41 (dm-II-20)

A white solid (36.9%) from acid 40 and 2,2,2-trifluoroethanol: mp188-190° C.; IR (KBr) 3443, 3277, 1710, 1600, 1492, 1366, 1280, 1156cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 3.18 (s, 1H), 4.08 (d, 1H, J=12.5 Hz),4.67 (m, 1H), 4.82 (m, 1H), 5.98 (d, 1H, J=12.5 Hz), 7.37-7.40 (m, 2H),7.44-7.51 (m, 3H), 7.56-7.59 (m, 2H), 7.78 (dd, 1H, J=1.5 Hz, 8.5 Hz);MS (EI) m/e (rel intensity) 409 (M⁺, 28). Anal. Calcd. ForC₂₂H₁₄N₃O₂F₃.0.25H₂O: C, 63.82; H, 3.72; N, 10.16. Found: C, 63.89; H,3.37; N, 9.94.

The bromide 1 was reacted with diethylphosphorochloridate in thepresence of sodium hydride, followed by addition of t-butylisocyanoacetate to provide the ester 42. This was converted into thetrimethylsilylacetyleno compound 43 under standard conditions(Pd-mediated, Heck-type coupling).⁸ Treatment of 43 with fluoride gavethe title compound 44.

Procedure for XLi225

t-Butyl8-bromo-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate42.

This benzodiazepine 42 was obtained in 40% yield from 1¹ analogous tothe literature procedure² as a white solid. 42 (XLi223): mp: 222°-223°C.; IR (KBr) 2975, 2358, 1717, 1608, 1557, 1277, 1073, 908, 696, 652cm⁻¹; ¹H NMR (CDCl₃) δ 1.60 (s, 9H), 4.03 (d, 1H, J=12.5 Hz), 6.08 (d,1H, J=12.4 Hz), 7.35-7.52 (m, 7H), 7.58 (d, 1H, J=2.2 Hz), 7.80 (dd, 1H,J=2.22 Hz and 8.55 Hz), 7.93 (s, 1H);

t-Butyl-8-trimethylsilylacetylenyl-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]-diazepine-3-carboxylate43 (XLi 224).^(4,5,8)

A mixture of bromide 42 (1 g, 2.28 mmol, trimethylsilylacetylene (559mg, 5.69 mmol) and bis(triphenylphosphine)-palladium-(I) acetate (55 mg,0.073 mmol) in a mixed solvent system of CH₃CN (15 mL) and anhydrous TEA(25 mL) was heated to reflux under argon. After stirring for 6 hours atreflux, the mixture was cooled to room temperature and the precipitatewhich formed was removed by filtration. The filtrate was concentratedunder reduced pressure and the residue was treated with a saturatedaqueous solution of NaHCO₃ (20 mL), and extracted with CHCl₃ (3×25 mL).The combined extracts were washed with brine and dried (Na₂SO₄). Afterremoval of solvent under reduced pressure, the residue was purified byflash chromatography (silica gel, EtOAc) to afford 43 (XLi224) as awhite solid (710 mg, 68.9%). mp:234°-236° C.; IR (KBr) 2973, 2357, 2154,1719, 1611, 1493, 1366, 1250, 1152, 1075, 946, 880 cm⁻¹; ¹H NMR (CDCl₃)δ 0.23 (s, 9H), 1.64 (s, 9H), 4.05 (d, 1H, J=12.7 Hz), 6.06 (d, 1H,J=12.4), 7.37-7.53 (m, 7H), 7.73 (dd, 1H, J=1.95 and 8.25 Hz), 7.92 (s,1 H); MS (EI) m/e (relative intensity) 427 (M⁺, 76), 412 (5), 381 (55),353 (100) 303 (10), 287 (7).

t-Butyl8-acetylenyl-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate44 (XLi 225).⁷

A solution of 43 (128 mg, 0.281 mmol), in THF (15 mL) was treated withBu₄NF.H₂O (100.04 mg, 0.38 mmol). The mixture which resulted was allowedto stir for 5 min at room temperature after which the mixture was addedto H₂O (10 mL) and extracted with EtOAc (3×15 mL). The combined organicextracts were washed with brine (15 mL) and dried (Na₂SO₄). Afterremoval of solvent under reduced pressure, the residue was purified by awash column (silica gel, EtOAc) to furnish 44 (XLi225) (92 mg, 85.4%) asa white solid: mp:221°-223° C.; IR (KBr) 3159, 3107, 2092, 1721, 1606cm⁻¹; ¹H NMR (CDCl₃) δ 1.62 (s, 9H), 3.21 (s, 1H), 4.12 (d, 1H, J=10.2Hz), 6.07 (d, 1H, J=12.5 Hz), 7.35-7.53 (m, 7H), 7.73 (dd, 1H, J=1.8 Hzand 8.3 Hz), 7.92 (s, 1H).

7-Bromo-2′-fluorobenzodiazepine 13 was hydrolyzed with aq 2 N sodiumhydroxide in EtOH and acidified to pH 4 by adding 1 N HCl to afford theacid 45. The acid, obtained from the ester 13, was stirred with CDI inDMF, followed by stirring with trifluoroethanol and DBU to provide theester 46 (JYI-049). This material 46 was heated withtrimethysilylacetylene in a Heck-type coupling reaction⁸ to provide thetrimethylsilyl analog 47 (JYI-053). The silyl group was removed from 47on treatment with tetrabutylammonium fluoride to furnish 48 (JYI-059) in70% yield.

Procedure:

8-Bromo-6-(2′-fluorophenyl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylicacid 45.

The ester 13 (1.0 g, 2.36 mmol) was dissolved in EtOH (80 mL) and 2 N aqNaOH (8 mL) was added to the solution. The mixture was stirred at rt for4 hours. After the EtOH was removed under reduced pressure, the solutionwas allowed to cool. The pH value was adjusted to 4 by adding 1 N HCldropwise. The mixture was filtered and the solid was washed with coldwater and ethyl ether. The solid was dried to afford 45 (0.96 g, 97%) asa white solid: mp 280° C. (dec); IR (KBr) 3419, 1740, 1611, 1491 cm⁻¹;¹H NMR (DMSO-d₆) δ 4.11 (bs, 1H), 5.99 (bs, 1 H), 7.20 (t, 1 H, J=8.5Hz), 7.32 (t, 1 H, J=7.5 Hz), 7.38 (d, 1 H, J=1.8 Hz), 7.55 (m, 2 H),7.84 (d, 1 H, J=8.7 Hz), 7.95 (dd, 1 H, J=8.6, 1.9 Hz), 8.35 (s, 1 H).MS (EI) m/e (relative intensity) 400 (72), 399 (85), 381 (100), 355(82).

Trifluoroethyl-8-bromo-6-(2′-fluorophenyl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate46 (JYI-049).

The carboxylic acid 45 (0.89 g, 2.23 mmol) was dissolved in dry DMF (20mL), after which CDI (0.72 g, 4.45 mmol) was added at rt and the mixturewas stirred for 12 hours. The trifluoroethanol (0.49 mL, 6.68 mmol) inDMF (1 mL) and DBU (0.37 mL, 2.45 mmol) in DMF (1 mL) were then added tothe mixture and stirring continued overnight. The solvent was evaporatedunder reduced pressure and the residue was purified by flashchromatography (silica gel, hexanes/EtOAc:3/1) to afford 46 (JYI-049,0.81 g, 76%) as a white solid: mp 223-224° C.; IR (CHCl₃) 3063, 1732,1611, 1492 cm⁻¹; ¹H NMR (CDCl₃) δ 4.16 (bs, 1 H), 4.80 (bs, 2 H), 6.07(bs, 1 H), 7.06 (dt, 1 H, J=8.3, 0.9 Hz), 7.30 (m, 2 H), 7.48 (m, 2 H),7.68 (dt, 1 H, J=7.6, 1.8 Hz), 7.80 (dd, 1 H, J=8.6, 2.1 Hz), 8.11 (s, 1H). MS (EI) m/e (relative intensity) 483 (38), 383 (64), 355 (100).Anal. Calcd. for C₂₀H₁₂N₃O₂F₄Br: C, 49.81; H, 2.51; N, 8.71. Found: C,49.97; H, 2.44; N, 8.68.

Trifluoroethyl-8-trimethylsilylacetylenyl-6-(2′-fluorophenyl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate47 (JYI-053).

A mixture of bromide 46 (JYI-049, 482 mg, 1.0 mmol),trimethylsilylacetylene (0.28 mL, 2.0 mmol) andbis(triphenylphosphine)palladium (II) acetate (75 mg, 0.1 mmol) in amixed solvent system of CH₃CN (25 mL) and anhydrous triethylamine (25mL) was heated to reflux under argon. After stirring for 12 h at reflux,the mixture was cooled to room temperature and the precipitate whichformed was removed by filtration. The filtrate was concentrated underreduced pressure and the residue was treated with a saturated aqsolution of NaHCO₃ (40 mL), and extracted with CHCl₃ (3×100 mL). Thecombined organic extracts were washed with brine (2×50 mL) and dried(Na₂SO₄). After removal of solvent under reduced pressure, the residuewas purified by flash chromatography (silica gel, hexanes/EtOAc:3/1) toafford 47 (JYI-053, 360 mg, 76%) as a gray solid: mp 220-221° C.; IR(CHCl₃) 2960, 1741, 1612, 1496 cm⁻¹; ¹H NMR (CDCl₃) δ 0.25 (s, 9 H),4.12 (bs, 1 H), 4.82 (bs, 2 H), 6.10 (bs, 1 H), 7.06 (t, 1 H, J=8.3 Hz),7.30 (m, 1 H), 7.48 (m, 2 H), 7.56 (d, 1 H, J=8.3 Hz), 7.67 (m, 1 H),7.73 (dd, 1 H, J=8.3, 1.8 Hz), 8.02 (s, 1 H); MS (EI) m/e (relativeintensity) 499 (52), 399 (45), 371 (100), 235 (21), 178 (36). Anal.Calcd. for C₂₅H₂₁N₃O₂F₄Si: C, 60.11; H, 4.24; N, 8.41. Found: C, 60.27;H, 4.22; N, 8.33.

Trifluoroethyl-8-acetyleno-6-(2′-fluorophenyl)-4H-benzo[f]imidazo-[1,5-a][1,4]diazepine-3-carboxylate48 (JYI-059).

A solution of 47 (JYI-053, 475 mg, 1.0 mmol) in THF (15 mL) was treatedwith Bu₄NF (2 mL, 1.0M solution in THF). The mixture, which resulted,was allowed to stir for 5 min at room temperature after which themixture was added to H₂O (5 mL) and extracted with EtOAc (3×10 mL). Thecombined organic extracts were washed with brine (2×10 mL) and dried(Na₂SO₄). The solvent was removed under reduced pressure and the residuewas recrystallized from ethyl acetate/hexanes to afford 48 (JYI-059, 299mg, 70%) as a pale yellow solid: mp 192-193° C.; IR (CHCl₃) 3295, 3052,1741, 1612, 1494, 1277, 1159 cm⁻¹; ¹H NMR (CDCl₃) δ 3.14 (s, 1 H), 4.17(bs, 1 H), 4.78 (bs 2 H), 4.47 (s, 1 H), 6.05 (bs, 1 H), 7.05 (dt, 1 H,J=8.3, 0.8 Hz), 7.30 (m, 1 H), 7.48 (m, 2H), 7.60 (d, 1 H, J=8.3 Hz),7.68 (dt, 1 H, J=7.6, 1.8 Hz), 7.76 (dd, 1 H, J=10.1, 1.8 Hz), 8.02 (s,1 H); MS (EI) m/e (relative intensity) 427 (37), 327 (26), 299 (100),178 (50). Anal. Calcd. for C₂₂H₁₃N₃O₂F₄: C, 61.83; H, 3.07; N, 9.83.Found: C, 61.94; H, 3.03; N, 9.68.

Ethyl amido oxime (59.5 mg, 0.676 mmol) was added to a stirredsuspension of powdered 4A molecular sieves (75 mg) in anhydrous THF (15mL) under nitrogen. After the mixture was stirred at rt for 10 min, NaH(27 mg of 60% in mineral oil, 0.676 mmol) was added to the mixture.After the mixture was stirred for a further 30 min, a solution of theforgoing ester 7 (XHeII-053, 120 mg, 0.338 mmol) in THF (20 mL) wasadded. The mixture which resulted was heated to reflux for 8 hr. It wascooled to rt, after which acetic acid (40.6 mg, 0.676 mmol) was added.After the solution was stirred for 10 min, the mixture was filteredthrough celite. The filtrate was diluted with CH₂Cl₂ (50 mL) and washedwith water, brine and dried (K₂CO₃). Evaporation of the solvent underreduced pressure afforded a pale yellow solid, which was purified byflash column chromatography (silica gel, EtOAc/hexane, 2:3) to furnish51 as a white solid (PS-1-26, 52 mg, 40%). mp: 221-222° C.; IR (KBr)3297, 3105, 1631, 1570, 1495, 1310, 938 cm⁻¹; ¹H NMR (CDCl₃) δ 8.07 (s,1H), 7.80 (dd, 1H, J=8.4 Hz, J=1.8 Hz), 7.64-7.60 (m, 2H), 7.53-7.37 (m,5H), 6.12 (d, 1H, J=12.9 Hz), 4.21 (d, 1H, J=12.9 Hz), 3.20 (s, 1H),2.88 and 2.83 (ABq, 2H, J=7.6 Hz), 1.41 (t, 3H, J=7.6 Hz); ¹³C NMR(CDCl₃) δ 171.8, 170.6, 168.8, 139.1, 136.6, 135.8, 135.4 (2C), 135.1,130.7, 129.3 (2C), 128.3 (2C), 128.1, 124.7, 122.7, 121.6, 81.2, 80.0,44.7, 19.7, 11.5; MS (m/z) 379 (100).

This compound 49 (PS-1-27) was obtained in 47% yield from 5 (dm-1-70)analogous to the procedure employed in [0085] as a white solid. mp: 210°C.; IR (KBr) 3106, 1631, 1563, 1493, 1147, 931, 698 cm⁻¹; ¹H NMR (CDCl₃)δ 8.06 (s, 1H), 7.84 (dd, 1H, J=8.6 Hz, J=2.25 Hz), 7.63-7.38 (m, 7H),6.13 (d, 1H, J=12.9 Hz), 4.21 (d, 1H, J=12.9 Hz), 3.20 (s, 1H), 2.88 and2.83 (ABq, 2H, J=7.6 Hz), 1.41 (t, 3H, J=7.6 Hz); MS (m/z) 435 (100).

To the suspension of compound 49 (PS-1-27, 0.5 g, 1.15 mmol) inacetonitrile (30 mL) and triethylamine (80 mL) was addedbis(triphenylphosphine)palladium (II) acetate (0.086 g, 0.115 mmol). Thesolution was degassed and trimethylsilylacetylene (0.33 mL, 2.3 mmol)added. The mixture was heated to reflux and stirred overnight. Afterremoval of the solvent, the residue was dissolved in CH₂Cl₂ and washedwith a saturated aqueous solution NaHCO₃ and brine. The organic layerwas dried (Na₂SO₄) filtered and concentrated under vacuum. The residuewas purified by flash column chromatography (EtOAc:hexane 2:3) tofurnish the trimethylsilyl analog 50 (PS-1-28, 380 mg, 73%) as a paleyellow solid: mp: 193-194° C.; IR (KBr) 3106, 2960, 2149, 1630, 1567,1493, 938, 851, 701 cm⁻¹; ¹H NMR (300 Hz, CDCl₃) δ 8.07 (s, 1H), 7.78(dd, 1H, J=1.86, 8.34 Hz), 7.61-7.38 (m, 7H), 6.11 (d, J=12.78 Hz), 4.19(d, J=12.78 Hz), 2.88 and 2.83 (ABq, 2H, J=7.56 Hz), 1.41 (t, 3H, J=7.56Hz), 0.25 (s, 9H).

The bromide 20 available from references 9 and 10 was reacted withtrimethylsilyacetylene in the presence of a palladium catalyst toprovide trimethylsilyl analog 52. This product was methylated withmethyl iodide/sodium hydride to give the N-methyl benzodiazepine 54 (XLi351). This was subjected to fluoride-mediated desilation to furnish 53(XLi 350) and 55 (XLi 352).

Procedure for XLi 350 and XLi 352

7-Trimethylsilylacetyleno-5-phenyl-(2′-chlorophenyl)1,3-dihydrobenzo[e]-1,4-diazepin-2-one52 (XLi 343).^(4,5,8)

A mixture of 20¹ (500 mg, 1.43 mmole) available from references 9 and 10in triethyl amine (10 mL) and CH₃CN (16 mL) withtrimethyl-silylacetylene (126 mg, 1.28 mmole) andbis(triphenylphosphine)palladium (II) acetate (64.3 mg, 0.086 mmol) washeated to reflux under nitrogen. After 6 hours, the reaction mixture wascooled to room temperature and filtered. The filtrate was concentratedunder vacuum and the residue was treated with a saturated aqueous NaHCO₃solution (15 mL), and extracted with CH₂Cl₂ (3×20 mL). The organiclayers were combined and washed with brine and dried (Na₂SO₄). Afterremoval of solvent under reduced pressure, the residue was purified viaflash chromatography (silica gel, EtOAc/hexanes:1/1) to furnish 52 as ayellow powder (310 mg, 59%): mp: 225.8-228.2° C.; IR (KBr) 2953, 2358,1685, 1616, 1490, 1328, 1248, 1058, 1011, 841, 746 cm⁻¹, ¹H NMR (CDCl₃)δ 0.21 (s, 9H), 4.38 (s, 2H), 7.41 (d, 1H, J=8.37 Hz), 7.19-7.52 (br,7H), 8.11 (s, 1H); MS (EI) m/e (relative intensity) 366 (M⁺, 100),331(59), 229(18), 161(26).

7-Acetyleno-5-phenyl-(2′-chlorophenyl)-1,3-dihydro-benzo[e]-1,4-diazepin-2-one53 (XLi 350):⁷ A solution of 52 (150 mg, 0.408 mol) in THF (30 mL) wastreated with tetrabutylammonium fluoride (1M in THF). The mixture wasstirred for 20 minutes at room temperature before water (30 mL) wasadded. The mixture was then extracted with EtOAc (3×30 mL). The combinedorganic extracts were washed with brine and dried over (Na₂SO₄). Thesolvent was removed under vacuum and the residue which resulted waspassed through a wash column (silica gel, EtOAc/hexanes:4/1) to give 55as light yellow crystals (110 mg, 95.2%); mp: 215° C.; IR (KBr) 3290,1685, 1615, 1491, 1328, 731 cm⁻¹, ¹H NMR (CDCl₃) δ 3.06 (s, 1H), 4.40(s, 3H), 7.03-7.61 (m, 7H), 7.58-7.86 (m, 2H), 7.99 (s, 1H); MS (EI) m/e(relative intensity) 294 (M⁺, 100), 266(75), 265(87), 259(83), 231(40),201(24), 176(23).

1-Methyl-7-trimethylsilylacetyleno-5-phenyl-(2′-chlorophenyl)-1,3-dihydro-benzo[e]-1,4-diazepin-2-one54 (XLi 351).7

A mixture of 52 (300 mg, 0.82 mmol) was dissolved in dry THF (40 mL) at0° C. and NaH (60% in mineral oil, 50 mg, 1.25 mmol) was added to thesolution in one portion. The slurry was then stirred for 20 min at 0° C.and CH₃₁ (139 mg, 0.98 mmol) was added to the mixture and it was warmedup to room temperature. After the mixture stirred for 3 hours at roomtemperature, the THF was then removed under reduced pressure. Theresidue was purified by flash chromatography [hexanes/EtOAc (1:4)] toprovide the title compound 54 (260 mg, 83%) as a white solid: mp:196.9-198° C.; IR (KBr) 2953, 1676, 1611, 1489, 1346, 1125, 1078, 913,742 cm⁻¹; ¹HNMR (CDCl₃) δ(ppm) 0.21(s, 9H) 3.46 (s, 3H), 3.54 (d, 1H,J=10.9 Hz), 4.60 (d, 1H, J=10.8 Hz), 7.20-7.43 (m, 5H), 7.58-7.65 (m,3H). MS (EI) m/e (relative intensity) 380(M⁺, 8), 366(10), 308(100),280(88), 273(97), 245(61).

1-Methyl-7-acetyleno-5-phenyl-(2′-chlorophenyl)-1,3-dihydro-benzo[e]-1,4-diazepin-2-one55 (XLi 352):⁷

A solution of 54 (100 mg, 0.262) in THF (30 mL) was treated withtetrabutylammonium fluoride (1M in THF). The mixture was stirred for 20minutes at room temperature before water (30 mL) was added. The mixturewas then extracted with EtOAc (3×30 mL). The combined organic extractswere washed with brine and dried (Na₂SO₄). The solvent was removed undervacuum and the residue which resulted was passed through a wash column(silica gel, EtOAc/hexanes:4/1) to give 55 as light yellow crystals (71mg, 90%): mp: 95.6-98.1° C.; IR (KBr) 2953, 1677, 1489, 1346, 1091, 791,749 cm⁻¹, ¹H NMR (CDCl₃) δ (ppm) 3.05(s, 1H), 3.46 (s, 3H), 3.83 (d, 1H,J=10.5 Hz), 4.87 (d, 1H, J=9.33 Hz), 5.28 (s, 1H), 7.20-7.43 (m, 5H),7.58-7.86 (m, 2H); MS (EI) m/e (relative intensity) 308(M⁺, 100),294(19), 280(82), 273(99), 249(28), 245(61), 229(29), 201(32), 189(43).

7-Trimethylsilylacetyleno-5-(2′-fluorophenyl)-1,3-dihydrobenzo[e]-1,4-diazepine-2-one56 (JYI-55).

A mixture of bromide 12 (1.6 g, 5.0 mmol), trimethylsilyl-acetylene (3.0mL, 21.0 mmol) and bis(triphenylphosphine)palladium (II) acetate (375mg, 0.5 mmol) in a mixed solvent system of CH₃CN (60 mL) and anhydroustriethylamine (40 mL) was heated to reflux under argon. After stirringfor 3 h at reflux, the mixture was cooled to room temperature and theprecipitate which formed was removed by filtration. The filtrate wasconcentrated under reduced pressure and the residue was treated with asaturated aq solution of NaHCO₃ (100 mL), and extracted with CHCl₃(3×200 mL). The combined organic extracts were washed with brine (2×100mL) and dried (Na₂SO₄). After removal of solvent under reduced pressure,the residue was purified by flash chromatography (silica gel,hexanes/EtOAc:2/1) to afford 56 (JYI-55, 794 mg, 47%) as a gray solid:mp 168.5-169.5° C.; IR (CHCl₃) 3202, 3113, 2955, 1686, 1612, 1490 cm⁻¹;¹H NMR (CDCl₃) δ 0.22 (s, 9 H), 4.38 (s, 2 H), 7.04-7.33 (m, 3 H), 7.34(s, 1 H), 7.45-7.53 (m, 1 H), 7.56-7.62 (m, 2 H), 8.73 (bs, 1 H). MS(EI) m/e (relative intensity) 350 (94), 322 (100), 167 (41), 153 (37).Anal. Calcd. for C₂₀H₁₉N₂OFSi: C, 68.54; H, 5.46; N, 7.99. Found: C,68.23; H, 5.40; N, 8.34.

7-Acetyleno-5-(2′-fluorophenyl)-1,3-dihydrobenzo[e]1,4-diazepine-2-one57 (JYI-60).

A solution of 56 (JYI-55, 700 mg, 2.0 mmol) in THF (200 mL) was treatedwith Bu₄NF (2 mL, 1.0M solution in THF). The mixture, which resulted,was allowed to stir for 5 min at room temperature after which themixture was added to H₂O (5 mL) and extracted with EtOAc (3×10 mL). Thecombined organic extracts were washed with brine (2×10 mL) and dried(Na₂SO₄). After the solvent was removed under reduced pressure, theresidue was purified by flash chromatography (silica gel,hexanes/EtOAc:2/1) to afford 57 (JYI-60, 400 mg, 72%) as a pale yellowsolid: mp 208-209.5° C.; IR (CHCl₃) 3290, 3110, 2930, 1685, 1612, 1489cm⁻¹; ¹H NMR (CDCl₃) δ 3.04 (s, 1 H), 4.40 (s, 2 H), 7.06-7.28 (m, 3 H),7.38 (s, 1 H), 7.44-7.51 (m, 1 H), 7.59-7.62 (m, 2 H), 9.43 (bs, 1 H).MS (EI) m/e (relative intensity) 278 (80), 250 (100). Anal. Calcd. forC₁₇H₁₁N₂OF: C, 73.37; H, 3.98; N, 10.07. Found: C, 73.64; H, 3.92; N,9.78.

2-Amino-5-iodo-benzophenone was prepared from p-iodonitrobenzene andphenylacetonitrile according to the literature.¹¹2-Amino-5-chloro-benzophenone was commercially available from Acros. Thebenzodiazepine 60 was reacted with diethylphosphorochloridate in thepresence of sodium hydride, followed by the addition of ethylisocyanoacetate to provide the ester 62 (Hz120), as shown in Scheme 13.

Ethyl8-iodo-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate62.

A solution of benzodiazepine 60 (3 g, 8.3 mmol) in dry THF (36 mL) wascooled to 0° C. and a 60% dispersion of sodium hydride (0.70 g, 17.4mmol) was added in one portion. The mixture was allowed to warm to rtwith stirring and the stirring was continued at rt until no more bubbleswere evolved. The suspension was cooled to 0° C. after whichdiethylphosphorochloridate (2.29 g, 13.3 mmol) was added and thismixture was stirred for 30 min and allowed to warm to rt. The mixturewas stirred for an additional 1.5 hr. In another flask, a 60% dispersionof sodium hydride (0.70 g, 17.4 mmol) in mineral oil was added in dryTHF (36 mL) and cooled to 0° C. Ethyl isocyanoacetate (1.13 g, 9.94mmol) was added and the stirring was continued until no more bubbleswere evolved. This mixture was transferred to the above mixture at 0° C.The mixture was then stirred at rt for 6 h and quenched with HOAc (3.2mL). The mixture was partitioned between EtOAc (200 mL) and H₂O (50 mL).The organic layer was washed with brine and dried (Na₂SO₄). After thesolvent was removed under reduced pressure, the residue was purified byflash chromatography (silica gel, gradient elution, EtOAc:hexane 1:4,1:1, 4:1) to provide the ester 62 (Hz120) in 43% yield as a light brownsolid. mp: 221-222° C.; IR (KBr) 2977, 1717, 1608, 1489 cm⁻¹; ¹H NMR(DMSO-d₆) δ 1.31 (t, 3H, J=7.1 Hz), 4.10 (d, 1H, J=12.5 Hz), 4.29 (q,2H, J=6.7 Hz), 5.75 (d, 1H, J=12.4 Hz), 7.40-7.50 (m, 5H), 7.63 (d, 1H,J=1.8 Hz), 7.69 (d, 1H, J=8.5 Hz), 8.13 (dd, 1H, J=1.9, 8.5 Hz), 8.36(s, 1H); MS (EI) m/e (relative intensity) 458 (23), 457 (M⁺, 100), 411(62), 384 (29), 383 (100), 257 (29). Anal. Calcd. for C₂₀H₁₆IN₃O₂: C,52.53; H, 3.53; N, 9.19. Found: C, 52.57, H, 3.73; N, 8.64.

Ethyl8-chloro-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate63.

This ester 63 was obtained in 52% yield from 61 analogous to theprocedure employed in [0092] as a white solid. mp: 174-175° C. (lit.¹²174-175° C.); ¹HNMR (DMSO-d₆) δ 1.32 (t, 3H, J=7.1 Hz), 4.13 (d, 1H,J=12.3 Hz), 4.32 (q, 2H, J=6.7 Hz), 5.76 (d, 1H, J=12.3 Hz), 7.37-7.50(m, 6H), 7.86-8.38 (m, 2H), 8.74 (s, 1H).

6-Bromo-2-phenyl-4H-benzo[2,3-d]-1,3-oxazin-4-one 64.

The 2-amino-5-bromobenzoic acid (5 g, 23.1 mmol) was treated withbenzoyl chloride (237 mL, 2.04 mol) at 140° C. for 3 h. After thereaction mixture was cooled to rt, the crystals that formed werecollected by filtration and were washed with hexanes to provide 64 aslight brown needles (6.8 g, 97%): ¹H NMR (CDCl₃) δ 7.51-7.2 (m, 4H), 7.9(dd, 1H, J=2.3, 8.6 Hz), 8.30-8.33 (m, 2H), 8.8 (d, 1H, J=2.2 Hz); ¹³CNMR (CDCl₃) δ 158.19, 157.35, 145.75, 139.58, 132.82, 130.97, 129.77,128.82, 128.73, 128.29, 121.37, 118.27; MS (EI) m/e (relative intensity)303 (M⁺, 36), 301 (M⁺, 36), 259 (14), 257 (14), 226 (6), 224 (6), 178(9), 170 (9), 168 (9), 151 (4), 105 (100).

4-Bromo-2-(2′-thienylcarbonyl)-N-benzoylaniline 66 andbis-(2′-thienyl)-[5-bromo-2-(N-benzoyl)-amino]phenylmethanol 65.

The benzo-xazinone 64 (5.0 g, 16.6 mmol) was dissolved in dry THF (250mL) and cooled to −78° C. for 45 min. The 2-thienyllithium (18.21 mL of1M solution in THF) was added dropwise over 35 min and the reaction wasstirred at −78° C. for 1.2 h. Saturated aq NH₄Cl solution (25 mL) andEt₂O (30 mL) were then added. The organic layer was separated, washedwith brine and dried (MgSO₄). The solvent was removed under reducedpressure, and the residue was purified via flash chromatography (silicagel, hexanes/EtOAc: 1:0, 49:1, 20:1, 11:1, 5:1) to provide 66 as yellowcrystals and the alcohol 65. 66: ¹H NMR (CDCl₃) δ 7.23 (dd, 1H),7.52-7.56 (m, 3H), 7.66 (dd, 1H, J=0.99, 3.8 Hz), 7.82 (d, 1H, J=5.0Hz), 7.99-8.02 (m, 3H), 7.75 (d, 1H, J=9.0 Hz), 11.2 (s, 1H); ¹³C NMR(CDCl₃) δ 188.82, 165.45, 143.24, 138.79, 136.57, 135.90, 135.51,134.25, 134.03, 132.17, 128.81, 128.31, 127.26, 125.65, 123.45, 114.95;MS (EI) m/e (relative intensity) 387 (M⁺, 12), 385 (M⁺, 12), 276 (18),274 (18), 201 (7), 172 (7), 105 (100). 65: ¹H NMR (CDCl₃) δ 4.20 (s,1H), 6.82 (s, 2H), 6.96-7.01 (m, 3H), 7.33-7.38 (m, 7H), 7.65 (d, 2H,J=7.23 Hz), 8.43 (d, 1H, J=8.8 Hz), 9.92 (s, 1H); ¹³C NMR (CDCl₃) δ165.04, 148.94, 136.44, 135.49, 134.49, 132.34, 131.59, 131.40, 128.40,127.20, 126.89, 126.58, 124.18, 116.00, 79.35, 76.92, 76.50; MS (EI) m/e(relative intensity) 471 (M⁺, 54), 469 (M⁺, 51), 453 (100), 451 (93),348 (98), 346 (92), 316 (54), 314 (58), 282 (20), 280 (19), 267 (88),235 (12), 234 (12), 223 (15), 222 (17), 201 (56), 173 (20), 172 (12),158 (10), 129 (10).

5-Bromo-2-(2′-thienylcarbonyl)aniline 67.

The amide 66 (2 g, 635 mmol) was dissolved in EtOH (150 mL) and 20% NaOHsolution (30 mL) was added. The mixture was heated to reflux for 5 h andthe EtOH was removed under reduced pressure. The mixture was extractedwith EtOAc and the organic phases were combined, washed with brine anddried (Na₂SO₄). The solvent was removed under reduced pressure, and theresidue was purified via a wash column (silica gel, hexanes/EtOAc: 11:1to 4:1) to provide 67 as a bright yellow solid: ¹H NMR (DMSO-d₆) δ 6.28(br s, 2H), 6.82 (s, 1H), 6.90 (s, 1H), 7.26 (dd, 1H, J=3.8, 5.0 Hz),7.42 (dd, 1H, J=2.4, 8.9 Hz), 7.61 (dd, 1H, J=1.1, 3.8 Hz), 7.69 (dd,1H, J=2.4 Hz), 8.04 (dd, 1H, J=1.1, 5.0 Hz); ¹³C NMR (DMSO) δ 187.42,150.09, 143.87, 136.46, 134.75, 134.41, 133.93, 128.78, 119.36, 119.17,104.95; MS (EI) m/e (relative intensity) 283 (M⁺, 59), 282 (M⁺, 87), 281(M⁺, 59), 280 (M⁺, 79), 250 (23), 248 (23), 201 (13), 199 (49), 197(48), 172 (25), 170 (23), 145 (13), 140 (1), 111 (100), 101 (33).

4-Bromo-2-(2′-thienylcarbonyl)-N-bromoacetylaniline 68.

The thienylaniline 67 (3.3 g, 11.7 mmol) and NaHCO₃ (2.9 g, 34.5 mmol)were suspended in dry CHCl₃ (180 mL) and cooled to 0° C. A solution ofbromoacetyl bromide (1.12 mL, 12.9 mmol) in dry CHCl₃ (30 mL) was addeddropwise over 20 min at 0° C. and the mixture was stirred at rt for 3 h.The CHCl₃ solution was then washed with aq NaHCO₃ (5%) and dried(Na₂SO₄). The CHCl₃ was removed under reduced pressure, and Et₂O wasadded to the flask. The solution was sonicated and filtered to provide68 as a light solid: mp: 144.0-146.5° C.; ¹H NMR (CDCl₃) δ 4.01 (s, 2H),7.23-7.26 (m, 1H), 7.24 (d, 1H), 7.65 (d, 1H), 7.74 (d, 1H), 7.84 (d,1H), 8.46 (d, 1H), 10.85 (br s, 1H); MS (EI) m/e (relative intensity)405 (M⁺, 69), 404 (40), 403 (M⁺, 100), 401 (M+, 66), 324 (39), 322 (38),310 (33), 308 (33), 292 (32), 283 (65), 282 (72), 281 (65), 280 (67),266 (10), 264 (10), 250 (34), 248 (35), 226 (55), 224 (55), 201 (43),199 (27), 197 (27), 173 (32), 111 (73).

7-Bromo-5-(2′-thienyl)-1,3-dihydrobenzo[e][1,4]diazepine 69 (JC184).

The bromoacetyl amide 68 (0.236 g, 0.586 mmol) was dissolved in asaturated solution of anhydrous ammonia in MeOH (50 mL) and the mixturewas heated to reflux for 6 h. After the MeOH was removed under reducedpressure, EtOAc was added to the residue. The solution was sonicated andthen filtered to provide 69 (JC184) as a light solid: MS (EI) m/e(relative intensity) 322 (M⁺, 54), 320 (M⁺, 53), 294 (100), 292 (98),211 (24), 185 (31), 140 (21). The material was used directly in the nextstep.

7-Trimethylsilylacetylenyl-5-(2′-thienyl)-1,3-dihydrobenzo[e][1,4]diazepine70 (JC207).

A mixture of 69 (1 g, 3.12 mmol) in CH₃CN (20 mL) and Et₃N (30 mL) wasdegassed and heated to reflux under nitrogen.Bis(triphenylphosphine)-palladium (II) acetate (0.26 g, 0.347 mmol) wasthen quickly added, followed by the addition of TMS acetylene (0.76 g,7.78 mmol). The mixture was stirred at reflux for 4 h and the solventwas removed under reduced pressure. Water (25 mL) and EtOAc (25 mL) wereadded to the residue and the mixture was filtered through celite toremove the organometallic species. The filtrate was then extracted withEtOAc and the organic phases were combined, washed with brine and dried(Na₂SO₄). The solvent was removed under reduced pressure and the residuewas purified via flash chromatography (silica gel, hexanes/EtOAc: 11:1,5:1) to provide 70 (JC207) as a light yellow solid: mp: 198.5-201° C.;MS (EI) m/e (relative intensity) 338 (M⁺, 68), 337 (M⁺, 28), 310 (100),295 (13), 161 (13), 147 (33), 105 (17). The material was used directlyin the next step.

7-Acetylenyl-5-(2′-thienyl)-1,3-dihydrobenzo[e][1,4]diazepine 72(JC208).

A solution of 70 (150 mg, 0.457 mmol) in THF (30 mL) was treated withtetrabutylammonium fluoride (1M in THF) at 0° C. for 5 minutes. Water(20 mL) was subsequently added to quench the reaction and the THF wasremoved under reduced pressure. The remaining aq solution was thenextracted with EtOAc and the organic phases were combined, washed withbrine and dried (Na₂SO₄). Upon removal of the solvent, Et₂O was added tothe residue which was sonicated and then filtered to provide the titlecompound 72 (JC208, 111 mg, 91%) as an ivory colored solid: mp: 214-216°C.; MS (EI) m/e (relative intensity) 266 (M⁺, 61), 265 (M⁺, 30), 238(100), 237 (49), 210 (13), 209 (10), 164 (6), 153 (7), 139 (7). Thismaterial was used in the next step.

1-N-methyl-7-trimethylsilylacetylenyl-5-(2′-thienyl)-1,3-dihydrobenzo[e][1,4]diazepine71 (JC209).

Thiophere 70 (500 g, 1.52 mmol) was dissolved in dry THF (25 mL) at 0°C. and NaH (60% in mineral oil, 76 mg, 1.50 mmol) was added to thesolution in one portion. After the mixture was stirred at 0° C. for 30min, MeI (0.14 mL, 2.25 mmol) was added and the ice bath was allowed towarm to rt. The mixture was allowed to stir for 3 h and the THF was thenremoved under reduced pressure. The residue was purified via flashchromatography (silica gel, hexanes/EtOAc 8:1, 4:1) to provide the titlecompound 71 (JC209) as a white solid: mp: 171.3-173.6° C.; ¹H NMR(CDCl₃) δ 0.26 (br s, 9H), 3.38 (s, 3H), 4.71 (d, 1H), 7.09 (dd, 1H,J=3.7, 5.0 Hz), 7.17 (dd, 1H, J=1.1, 3.7 Hz), 7.30 (s, 1H), 7.49 (dd,1H, J=1.1, 5.0 Hz), 7.65 (dd, 1H, J=2.0, 8.5 Hz), 7.75 (d, 1H); ¹³C NMR(CDCl₃) δ (CDCl₃) δ 170.12, 163.22, 143.65, 143.14, 134.69, 133.12,131.38, 130.14, 127.77, 127.47, 121.01, 119.10, 103.01, 95.66, 56.38,34.67; MS (EI) m/e (relative intensity) 352 (M⁺, 71), 351 (M⁺, 60), 337(10), 324 (100), 309 (24), 168 (28), 154 (38).

1-N-methyl-7-acetyleno-5-(2′-thienyl)-1,3-dihydrobenzo[e][1,4]diazepine73 (JC222).

The same procedure for preparing 72 (JC208) was applied to 73 (JC222)and a very light brown solid resulted: mp: 218.3-220.4° C.; ¹H NMR(CDCl₃) δ 3.16 (s, 1H), 3.39 (s, 3H), 3.78 (d, 1H, J=11.07 Hz), 4.72 (d,1H, J=5.9 Hz), 7.08 (dd, 1H, J=3.8, 5.0 Hz), 7.31 (d, 1H, J=8.6 Hz),7.49 (dd, 1H, J=1.0, 5.0 Hz), 7.67 (dd, 1H, J=2.0, 8.5 Hz), 7.79 (d, 1H,J=1.9 Hz); ¹³C NMR (CDCl₃) □ 171.04, 170.07, 163.12, 143.49, 134.79,133.50, 131.34, 130.25, 127.85, 127.46, 121.16, 117.99, 81.83, 78.30,56.34, 34.69. MS (EI) m/e (relative intensity) 281 (13), 280 (M⁺, 60),279 (51), 253(19), 252 (100), 251(2), 235 (11), 209(10).

Ethyl8-bromo-6-(2′-thienyl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate74 (JC217).

Dry THF (30 mL) was added to a flask containing the benzodiazepine 69(1.27 g, 3.96 mmol) and the solution was allowed to cool to 0° C. andNaH (60% in mineral oil, 0.191 g, 4.76 mmol) was quickly added. Themixture was stirred for 30 min at 0° C. and then removed from an icebath to stir another 1 h at rt. Prior to adding CIPO(OEt)₂ (1.06 g, 6.35mmol), the mixture was again pre-cooled to 0° C. The solution wasstirred another 3 h as the ice bath warmed to rt. Meanwhile, dry THF (10mL) was added to a second flask containing NaH (60% in mineral oil,0.229 g, 5.72 mmol). After the second mixture was cooled to 0° C.,CNCH₂CO₂Et was added dropwise and the solution continued to stir for 30min at 0° C. After both reaction mixtures were again pre-cooled to 0°C., the two solutions were combined under Ar via cannula and thesolution stirred at rt overnight. The reaction was quenched with icewater and worked up with EtOAc, and the combined organic phases werewashed with brine and dried (Na₂SO₄). The solvent was removed underreduced pressure and the residue was purified via flash chromatography(silica gel, hexanes:EtOAc 4:1, 1:1, 1:3) to provide the title compound74 (JC217) as an ivory solid (500 mg, 30% yield): mp: 204.0-205.3° C.;¹H NMR (CDCl₃) δ 1.45 (t, 3H, J=7.1, 14.3 Hz), 4.07 (d, 1H, J=8.8 Hz),4.44 (dd, 2H, J=3.8, 4.7 Hz), 5.98 (d, 1H, J=12.8 Hz), 7.05 (d, 1H, J=10Hz), 7.07 (s, 1H), 7.46-7.49 (m, 2H), 7.83 (dd, 1H, J=2.2, 8.5 Hz), 7.91(s, 1H), 7.96 (d, 1H, J=2.2 Hz): MS (EI) m/e (relative intensity) 418(M⁺, 15), 417 (M⁺, 68), 416 (M⁺, 15), 415 (M⁺, 64), 407 (22), 344 (26),343 (100), 342 (30), 341 (93), 293 (15), 291 (21), 262 (18), 235 (15),211 (12), 154 (10), 127 (11).

Ethyl8-trimethylsilylacetylenyl-6-(2-thienyl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate75 (JC220).

The same procedure for preparing 70 (JC207) was applied to 75 (JC220)and an ivory colored solid resulted: ¹H NMR (CDCl₃) δ 0.29 (s, 9H), 1.45(t, 3H, J=7.1, 14.3 Hz), 4.0 (d, 1H, J=18.1 Hz), 4.45 (dd, 2H, J=7.2,8.5 Hz), 5.97 (d, 1H, J=12.8 Hz), 7.06-7.11 (m, 2H), 7.49 (dd, 1H,J=1.2, 5.0 Hz), 7.52 (d, 1H, J=8.3 Hz), 7.77 (dd, 1H, J=1.9, 8.3 Hz),7.90 (d, 1H, J=1.8 Hz), 7.93 (s, 1H). MS (EI) m/e (relative intensity)433 (M⁺, 74), 387 (49), 359 (100), 277 (28), 262 (19), 235 (24), 172(19), 129(17).

Ethyl8-acetyleno-6-(2′-thienyl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate76 (JC221).

The same procedure for preparing 72 (JC208) was applied to 76 (JC221)and an ivory colored solid resulted: mp: >198° C.; ¹H NMR (CDCl₃) δ 1.43(t, 3H, J=4.3, 11.4 Hz), 3.25 (s, 1H), 4.10 (d, 1H, J=12.8 Hz) 4.40-4.49(m, 2H), 5.99 (d, 1H, J=12.9 Hz), 7.50 (d, 1H, J=5.0 Hz), 7.56 (d, 1H,J=8.3 Hz), 7.81 (dd, 1H, J=1.8, 8.3 Hz), 7.95 (s, 1H); MS (EI) m/e(relative intensity) 361, (M⁺, 24), 315 (35), 287 (100), 237 (26), 178(30), 153 (21), 126 (18). MS (EI) m/e (relative intensity) 361 (M⁺, 29),315 (41), 287 (100), 237 (31), 178 (40), 153 (26), 126 (21).

The benzodiazepine 1 was oxidized with 3-chloroperoxybenzoic acid(mCPBA) to form 77, followed by the addition of methylamine to affordamidine 78. N-Oxide 78 was reacted with trimethylsilyacetylene in thepresence of a palladium catalyst to provide the trimethylsilyl analog 79(Hz146) which was subjected to fluoride-mediated desilation to afford 80(Hz147), as shown in Scheme 15. In a related route, bromide 81 wasconverted into the trimethylsilylacetylene 82 (Hz141). This analog wasthen transformed into target 79 (Hz146) with mCPBA or the key target(Hz148) or treatment with fluoride (Scheme 16).

7-Bromo-4-oxy-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one

77. Bromide 1 (1.88 g, 5.95 mmol) was dissolved in CH₂Cl₂ (50 mL) andmCPBA (77% max) (1.76 g) was added at rt. The reaction mixture wasstirred overnight. The mixture was diluted with CH₂Cl₂ (80 mL) andwashed with a sat. solution of NaHCO₃ (50 mL), water (50 mL) and brine(40 mL). The organic layer was dried (Na₂SO₄) and concentrated. Theresidue was purified by flash chromatography (silica gel, EtOAc) toafford compound 77 in 90% yield as a white solid. mp: 230-231° C. (lit.³ 230-231° C.); ¹H NMR (CDCl₃) δ 4.69 (s, 2H), 7.16 (d, 1H, J=8.7 Hz),7.24 (d, 1H, J=2.1 Hz), 7.45 (m, 3H), 7.54 (dd, 1H, J=8.6, 2.2 Hz), 7.64(dd, 2H, J=7.3, 3.6 Hz), 10.02 (s, 1H).

(7-Bromo-4-oxy-5-phenyl-3H-benzo[e][1,4]diazepin-2-yl)-methylamine 78.

Methylamine (50 mL, 2 M in THF) was added to 77 (1.9 g, 5.7 mmol) in a100 mL round-bottom flask. The mixture was cooled to 0° C. after whichTiCl₄ (0.54 g, 2.86 mmol) was added dropwise. The reaction mixture wasallowed to warm to rt and stirred for 4 h. The mixture was quenched withwater (5 mL), diluted with EtOAc (100 mL) and washed with dilute NH₄OH.The organic layer was washed with water, brine and dried (Na₂SO₄). Afterthe solvent was removed under reduced pressure, the residue was purifiedby flash chromatography (silica gel, gradient elution, EtOAc, EtOAc:MeOH10:1) to provide 78 in 86% yield as a white solid. mp: 236-237° C. (lit.⁴ 242-243° C.); ¹H NMR (300 MHz, CDCl₃) δ 0.21 (s, 9H), 2.91 (s, 3H),4.17 (s, 1H), 4.85 (s, 1H), 7.13-7.66 (m, 9H).

(7-Trimethylsilylacetylenyl-4-oxy-5-phenyl-3H-benzo[e][1,4]diazepin-2-yl)-methyl-amine79 (Hz146).

Trimethylsilylacetylenyl analog 79 (Hz146) was obtained in 58% yieldfrom 78 analogous to the procedure employed in [0047] as a light graysolid. mp: 239-240° C.; IR (KBr) 3229, 3060, 2952, 2149, 1616, 1593,1462, 1238, 868 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 2.89 (d, 3H, J=4.4 Hz),4.14 (d, 1H, J=10.6 Hz), 4.78 (d, 1H, J=10.4 Hz), 7.15 (d, 1H, J=1.7Hz), 7.24-7.28 (m, 2H), 7.45 (m, 4H), 7.66 (m, 2H); MS (EI) m/e(relative intensity) 361 (M⁺, 48), 344 (100), 303 (31), 165(33).

(7-Acetylenyl-4-oxy-5-phenyl-3H-benzo[e][1,4]diazepin-2-yl)-methyl-amine80 (Hz147).

The 7-acetyleno target 80 was obtained in 90% yield from 79 analogous tothe procedure employed in [0048] as a light yellow solid. mp: 213-214°C.; IR (KBr) 3242, 3068, 2977, 1619, 1589, 1460, 1414 cm⁻¹; ¹H NMR (300MHz, CDCl₃) δ 2.89 (d, 2H, J=3.7 Hz), 2.98 (s, 1H), 4.13 (bs, 1H), 4.78(bs, 1H), 7.18-7.71 (m, 9H); MS (EI) m/e (relative intensity) 289 (M⁺,47), 272 (100), 231 (42).

(7-Bromo-5-phenyl-3H-benzo[e][1,4]diazepin-2-yl)-methyl-amine 81(Hz135).

Bromide 81 was obtained in 70% yield from 1 analogous to the procedureemployed in [0106] as a white solid. mp: 234-235° C.; IR (KBr) 3253,3076, 1609, 1571, 1415, 1326, 1230 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 2.62(s, 3H), 3.56 (bs, 1H), 4.68 (bs, 1H), 6.34 (s, 1H), 7.17 (d, 1H, J=8.7Hz), 7.36-7.81 (m, 7H); MS (EI) m/e (relative intensity) 329 (80), 328(M⁺, 100), 327 (82), 326 (92), 220 (38), 219(48), 218(46), 205 (38).

(7-Trimethylsilylacetylenyl-5-phenyl-3H-benzo[e][1,4]diazepin-2-yl)-methyl-amine82 (Hz141).

Trimethylsilylacetylenyl analog 82 (Hz141) was obtained in 73% yieldfrom 81 analogous to the procedure employed in [0047] as a light yellowsolid. mp: 210-211° C.; IR (KBr) 3257, 3079, 2956, 2150, 1619, 1610,1580, 1416, 1237, 880, 843 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 0.22 (s, 9H),2.59 (d, 3H, J=3.5 Hz), 3.56 (bs, 1H), 4.66 (bs, 1H), 6.39 (s, 1H), 7.21(d, 1H, J=8.4 Hz), 7.39-7.65 (m, 7H); MS (EI) m/e (relative intensity)345 (M⁺, 100), 344 (98), 164(50).

(7-Acetylenyl-4-oxy-5-phenyl-3H-benzo[e][1,4]diazepin-2-yl)-methylamine83 (Hz148).

The 7-acetyleno analog 83 (Hz148) was obtained in 92% yield from 82analogous to the procedure employed in [0048] as a white solid. mp:226-227° C.; IR (KBr) 3275, 3245, 3075, 2102, 1618, 1599, 1580, 1467,1416, 1333, 1235 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 2.65 (d, 3H, J=4.4 Hz),2.97 (s, 1H), 3.57 (bs, 1H), 4.65 (bs, 1H), 6.20 (d, 1H, J=3.7 Hz), 7.22(d, 1H, J=8.4 Hz), 7.42-7.58 (m, 7H). MS (EI) m/e (relative intensity)273 (M⁺, 100), 272 (98).

A suspension of7-bromo-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-thione 84¹⁵ (1.6 g,4.83 mmol), glycine (1.81 g, 24.2 mmol) and Na₂CO₃ (1.84 g, 17.4 mmol)in EtOH (38 mL)-H₂O (16 mL) was stirred at reflux for 5 h, poured intowater (100 mL), and then filtered to remove a small amount of7-bromo-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one which remained.The filtrate was extracted with CHCl₃. The CHCl₃ extract was discarded;the aqueous layer was adjusted to pH 4 with 2N HCl and then extractedwith CHCl₃ (3×25 mL). Evaporation of the CHCl₃ solution gave pure acid85 (1.2 g, 67%) as a yellow solid. Acid 85 (350 mg, 0.941 mmol) wassuspended in dry CH₂Cl₂ (10 mL) and DCC (223 mg, 1.08 mmol) was added.The suspension which resulted was stirred at 40° C. for 2 h and thencooled to 0° C. It was filtered, and the solvent was removed in vacuumto give8-bromo-2,4-dihydro-6-phenyl-1H-imidazo[1,2-a][1,4]benzodiazepin-1-one 3as a brown oil. The cyclized product 86 (ca. 250 mg) was dissolved indry benzene (6 mL), dimethylformamide diethylacetal (130 mg, 0.883 mmol)and triethylamine (89 mg, 0.883 mmol) were added. The solution whichresulted was stirred at room temperature for 1 h and the solvent wasremoved in vacuum, The residue was then crystallized from EtOAc-MeOH togive 87 (200 mg, 70%). A solution of 87 (180 mg, 0.440 mmol) in drytoluene (5 mL) was treated with 1-methyl piperazine (1 mL) and heated toreflux for 5 h. The solvent was removed in vacuum to give a gum whichcrystallized from CH₂Cl₂-Et₂O to furnish 88 (PS-1-35, 146 mg, 72%).mp>250° C.; IR (KBr) 3324, 2932, 2787, 1692, 1624, 1475, 1402, 1297,1137, 933 cm⁻¹; ¹H NMR (CDCl₃) δ 7.95 (d, 1H, J=8.8 Hz), 7.72 (dd, 1H,J=2.3 Hz, J=8.8 Hz), 7.58-7.55 (m, 2H), 7.49-7.37 (m, 4H), 7.17 (s, 1H),5.01 (d, 1H, J=12 Hz), 4.50-4.60 (m, 1H), 4.20-4.30 (m, 1H), 4.16 (d,1H, J=12 Hz), 3.50-3.58 (m, 2H), 2.40-2.60 (m, 4H), 2.34 (s, 3H); MS(m/z) 465 (100).

To the suspension of compound 88 (PS-1-35, 140 mg, 0.302 mmol) inacetonitrile (4 mL) and triethylamine (3 mL) was addedbis(triphenylphosphine)-palladium (II) acetate (22.6 mg, 0.03 mmol). Thesolution was degassed and trimethylsilylacetylene (0.1 mL, 0.7 mmol) wasadded. The mixture was heated to reflux and stirred overnight. Afterremoval of the solvent in vacuum, the residue was dissolved in CH₂Cl₂and washed with a saturated aqueous solution of NaHCO₃ and brine. Theorganic layer was dried (Na₂CO₃), filtered and concentrated undervacuum. The residue was purified by flash column chromatography(EtOAc:MeOH 9:1) to furnish the trimethylsilyl analogue 89 (PS-1-36, 100mg, 69%) as a pale yellow solid. mp>250° C.; IR (KBr) 3436, 2936, 2794,2154, 1682, 1625, 1489, 1136, 847 cm⁻¹; ¹H NMR (CDCl₃) δ 8.0 (d, 1H,J=8.5 Hz), 7.68 (dd, 1H, J=1.9 Hz, J=8.5 Hz), 7.55-7.59 (m, 2H),7.37-7.49 (m, 4H), 7.16 (s, 1H), 4.99 (d, 1H, J=12 Hz), 4.50-4.60 (m,1H), 4.20-4.30 (m, 1H), 4.13 (d, 1H, J=12.4 Hz), 3.48-3.58 (m, 2H),2.4-2.6 (m, 4H), 2.35 (s, 3H), 0.23 (s, 9H); MS (m/z) 482 (100).

A solution of the trimethylsilyl analog 89 (PS-1-36, 65 mg, 0.135 mmol)in THF (15 mL) was stirred with tetrabutylammonium fluoride hydrate (45mg, 0.175 mmol) at −5° C. for 5 min. After this, H₂O (5 mL) was added tothe solution to quench the reaction and stirring continued at lowtemperature for one half hour. The solution was extracted with EtOAc(3×40 mL), and the organic layer was washed with water. After removal ofthe solvent under reduced pressure, ethyl ether was added to the residueto precipitate a solid. The mixture was filtered and the solid waswashed with CHCl₃-Et₂O (ca 1:15) to provide the acetyl target 90(PS-1-37, 40 mg, 73%). mp 223-224° C.; IR (KBr) 3298, 2935, 2786, 1695,1628, 1364, 1136, 1002, 778 cm⁻¹; ¹H NMR (CDCl₃) δ 8.04 (d, 1H, J=8.5Hz), 7.71 (dd, 1H, J=1.9 Hz, J=8.5 Hz), 7.55-7.58 (m, 2H), 7.36-7.48 (m,4H), 7.17 (s, 1H), 5.0 (d, 1H, J=12.1 Hz), 4.5-4.6 (m, 1H), 4.2-4.3 (m,1H), 4.16 (d, 1H, J=12.1 Hz), 3.5-3.6 (m, 2H), 3.08 (s, 1H), 2.4-2.6 (m,4H), 2.35 (s, 3H); MS (m/z) (100).

The acid 27, obtained from the ester 5 (dm-1-70), was stirred with CDIin DMF, followed by stirring with 1,3-propanediol and DBU to provide 91(DMH-D-070, the dimer of dm-1-70). This was converted into thetrimethylsilylacetylenyl compound 92 (DMH-D-048, the dimer of XLiXHe048)under standard conditions (Pd-mediated, Heck-type coupling).^(4,7,8) Thebisacetylene 93 (DMH-D-053, the dimer of XHeII-053) was easily obtainedby treatment of trimethylsilyl compound 92 with fluoride anion as shownin Scheme 18.⁷

8-Bromo-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylicacid 27.

The ester 5 (2 g) was dissolved in EtOH (50 mL) and aq sodium hydroxide(10 mL, 2N) was added to the solution. The mixture was heated to refluxfor half an hour. After the EtOH was removed under reduced pressure, thesolution was allowed to cool. The pH value was adjusted to 4 by adding10% aq HCl dropwise. The mixture was filtered and the solid was washedwith water and ethyl ether. The solid was dried to provide 27 (1.8 g,96.6%): mp>250° C.; IR (KBr) 3450 (b), 2844, 1707, 1615, 1493, 1166, 700cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ 4.14 (d, 1H, J=12.6 Hz), 5.79 (d, 1H,12.6 Hz), 7.41-7.54 (m, 6H), 7.88 (d, 1H, J=8.7 Hz), 8.03 (dd, 1H, J=8.7Hz, J=2.1 Hz), 8.47 (s, 1H); MS (EI) m/e (rel intensity) 381 (M⁺, 20),383 (19).

1,3-Bis(8-bromo-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carb-oxy)propyldiester 91 (DMH-D-070).

The carboxylic acid 27 (2 g, 5.2 mmol) was dissolved in DMF (20 mL),after which CDI (1.02 g, 6.3 mmol) was added at rt and the mixture wasstirred for 2 h. Then 1,3-propanediol (0.19 mL, 2.6 mmol) and DBU (0.78mL, 5.2 mmol) were added to the mixture and stirring continuedovernight. The reaction solution was then cooled with an ice-water bath,after which water was added to precipitate a solid. This material waspurified further by flash chromatography on silica gel (gradientelution, EtOAc:EtOH 20:1, 15:1, 10:1) to provide the bisbromide 91(DMH-D-070) as a white solid (1.3 g, 61.9%): mp 187.5-189° C.; IR (KBr)3112, 2968, 1708, 1610, 1559, 1491, 1269, 1160, 1123, 1073 cm⁻¹; ¹H NMR(300 MHz, CDCl₃) δ 2.35 (m, 2H), 4.08 (d, 2H, J=12.6 Hz), 4.55 (m, 4H),6.05 (d, 2H, J=12.6 Hz), 7.37-7.53 (m, 12H), 7.6 (d, 2H, J=2.1 Hz), 7.81(dd, 2H, J=2.1 Hz, 8.6 Hz), 7.93 (s, 2H); ¹³C NMR (75.5 MHz, CDCl₃) δ28.2, 44.9, 61.4, 120.7, 124.2, 128.3, 129.0, 129.3, 129.6, 130.6,134.1, 134.4, 134.7, 135.0, 138.9, 138.9, 162.6, 167.9; MS (FAB, NBA)m/e (rel intensity) 803 (M⁺+1, 15); Anal. Calcd. For C₃₉H₂₈N₆O₄Br₂: C,58.23; H, 3.51; N, 10.45. Found: C, 57.92; H, 3.43; N, 10.29.

1,3-Bis(8-trimethylsilylacetylenyl-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]-diazepine-3-carboxy)propyldiester 92 (DMH-D-048)^(4,7,8)

To a suspension of bisbromide 91 (1.005 g, 1.25 mmol) in acetonitrile(50 mL) and triethylamine (65 mL), was addedbis(triphenylphosphine)-palladium (II) acetate (0.15 g, 0.2 mmol). Thesolution was degassed and trimethylsilylacetylene (0.7 mL, 5 mmol) wasadded after which it was degassed again. The mixture was heated toreflux and stirring maintained overnight. After removal of the solventunder reduced pressure, the residue was dissolved in CH₂Cl₂ and washedwith water. 3-Mecaptopropyl functionalized silica gel (0.6 g) was addedinto the organic layer and stirring continued for 1 hour. The silicagel/Pd complex was removed by filtration and the filtrate wasconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (gradient elution, EtOAc:EtOH 20:1,15:1, 10:1) to furnish the bistrimethylsilyl dimer 92 (DMH-D-048, 680mg, 60.8%) as a white solid: mp 169-172° C.; IR (KBr) 3449, 2950, 1725,1720, 1715, 1496, 1250, 1160, 1080, 847 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ0.25 (s, 18H), 2.35 (m, 2H), 4.05 (d, 2H, J=12.6 Hz), 4.55 (m, 4H), 6.02(d, 2H, J=12.6 Hz), 7.37-7.55 (m, 14H), 7.75 (dd, 2H, J=1.8 Hz, 8.4 Hz),7.94 (s, 2H); ¹³C NMR (75.5 MHz, CDCl₃) δ −0.3, 28.3, 44.9, 61.4, 97.4,102.3, 122.4, 122.6, 128.0, 128.3, 129.0, 129.4, 130.5, 134.1, 134.9,135.1, 139.0, 139.2, 139.2, 162.6, 168.5; MS (FAB, NBA) m/e (relintensity) 839 (M⁺+1, 100); Anal. Calcd. For C₄₉H₄₆N₆O₄Si₂: C, 70.14; H,5.53; N, 10.02. Found: C, 69.97; H, 5.35; N, 9.77.

1,3-Bis(8-acetylenyl-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxy)propyldiester 93 (DMH-D-053)⁷

A solution of bistrimethylsilyl dimer 92 (330 mg, 0.4 mmol) in THF (70mL) was stirred with tetrabutylammonium fluoride hydrate (250 mg, 0.96mmol) at −78° C. for 5 min. After this, H₂O (35 mL) was added to thesolution to quench the reaction and stirring continued at lowtemperature for one half hour. The solution was extracted with EtOAc(3×100 mL), and the organic layer was washed with water. After removalof the solvent under reduced pressure, ethyl ether was added to theresidue to precipitate a solid. The mixture was filtered and the solidwas washed with CHCl₃-Et₂O (ca 1:15), the bisacetylenyl dimer 93(DMH-D-053, 220 mg, 80%) was obtained as a yellow solid: mp 172-175° C.;IR (KBr) 3450, 3280, 2950, 1720, 1715, 1495, 1250, 1120, 1050 cm⁻¹; ¹HNMR (300 MHz, CDCl₃) δ 2.35 (m, 2H), 3.18 (s, 2H), 4.08 (d, 2H, J=12.3Hz), 4.56 (m, 4H), 6.04 (d, 2H, J=12.6 Hz), 7.36-7.59 (m, 14H), 7.78(dd, 2H, J=8.4 Hz, 1.7 Hz), 7.95 (s, 2H); ¹³C NMR (75.5 MHz, CDCl₃) δ28.8, 45.4, 61.9, 80.2, 81.3, 121.4, 122.7, 128.1, 128.3, 129.0, 129.3,130.5, 134.2, 135.2, 135.3, 135.6, 138.9, 139.2, 162.6, 168.5; MS (FAB,NBA) m/e (rel intensity) 695 (M⁺+1, 100).

The 5-carbon linker bisbromide 94 (dm-II-26),bis-trimethylsilylacetylenyl dimer 95 (dm-II-41) and bisacetylene dimer96 (dm-II-97), which are analogues of dimers DMH-D-070, DMH-D-048 andDMH-D-053, respectively, were prepared from acid 27 under the sameconditions employed for preparing dimers 91 (DMH-D-070), 92 (DMH-D-048)and 93 (DMH-D-053), respectively, by using 1,5-pentanediol in place of1,3-propanediol (Scheme 19).

1,5-Bis(8-bromo-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carb-oxy)pentyldiester 94 (dm-II-26)

A yellow powder (63.2%): mp 172-175° C.; IR (KBr) 3112, 2970, 1721,1609, 1490, 1267, 1158, 1075, 754, 697 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ1.62 (m, 2H), 1.90 (m, 4H), 4.07 (d, 2H, J=12.6 Hz), 4.39 (m, 4H), 6.05(d, 2H, J=12.6 Hz), 7.37-7.53 (m, 12H), 7.58 (d, 2H, J=2.1 Hz), 7.78(dd, 2H, J=2.1 Hz, 8.6 Hz), 7.92 (s, 2H); ¹³C NMR (75.5 MHz, CDCl₃) δ22.5, 28.4, 44.9, 64.5, 120.7, 124.2, 128.3, 129.2, 129.3, 129.6, 130.6,134.0, 134.5, 134.6, 135.0, 138.8, 138.9, 162.8, 167.9; MS (FAB, NBA)m/e (rel intensity) 831 (M⁺+1, 5). Anal. Calcd. ForC₄₁H₃₂N₆O₄Br₂.0.25H₂O: C, 58.95; H, 3.89; N, 10.07. Found: C, 58.69; H,3.74; N, 9.70.

1,5-Bis(8-trimethylsilylacetylenyl-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]-diazepine-3-carboxy)pentyldiester 95 (dm-II-41)

A yellow solid (58.1%): mp 154-156° C.; IR (KBr) 3426, 2955, 1727, 1720,1612, 1495, 1251, 1174, 1076, 846 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 0.25(s, 18H), 1.63(m, 2H), 1.90 (m, 4H), 4.05 (d, 2H, J=12.6 Hz), 4.39 (m,4H), 6.03 (d, 2H, J=12.6 Hz), 7.40-7.54 (m, 14H), 7.75 (dd, 2H, J=1.8Hz, 8.4 Hz), 7.93 (s, 2H); ¹³C NMR (75.5 MHz, CDCl₃) δ −0.3, 22.5, 28.4,44.9, 64.5, 97.4, 102.3, 122.4, 122.6, 128.0, 128.3, 129.2, 129.4,130.5, 134.1, 135.0, 135.1, 135.1, 138.9, 139.3, 162.8, 168.5; MS (FAB,NBA) m/e (rel intensity) 867 (M⁺+1, 100).

1,5-Bis(8-acetylenyl-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxy)pentyl diester 96 (dm-III-97).

A yellow solid: mp 150-153° C.; IR (KBr) 3290, 2953, 1718, 1611, 1493,1253, 1172, 1120, 1076 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 1.62 (m, 2H),1.90 (m, 4H), 3.18 (s, 2H), 4.07 (d, 2H, J=12.3 Hz), 4.38 (m, 4H), 6.04(d, 2H, J=12.3 Hz), 7.36-7.58 (m, 14H), 7.77 (dd, 2H, J=8.4 Hz, 1.6 Hz),7.94 (s, 2H); ¹³C NMR (75.5 MHz, CDCl₃) δ 22.5, 28.4, 44.9, 64.5, 79.8,81.3, 121.3, 122.7, 128.1, 128.3, 129.2, 129.3, 130.5, 134.1, 135.2,135.3, 135.6, 138.8, 139.2, 162.8, 168.5; MS (FAB, NBA) m/e (relintensity) 723 (M⁺+1, 13).

In order to improve the water solubility of the dimers, theoxygen-containing 5-atom linked dimers 97 (dm-III-93), 98 (dm-II-94) and99 (dm-III-96), were designed and prepared from acid 27 under the sameconditions employed for preparation of dimers DMH-D-070, DMH-D-048 andDMH-D-053, respectively, by replacing 1,3-propanediol with diethyleneglycol (Scheme 20).

Bis(8-bromo-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxy)diethyleneglycol diester 97 (dm-III-93)

A yellow solid (93.7%): mp 165-168° C.; IR (KBr) 3060, 2956, 1725, 1610,1558, 1491, 1267, 1161, 1123, 1074 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 3.93(t, 4H, J=4.8 Hz), 4.06 (d, 2H, J=12.6 Hz), 4.54 (m, 4H), 6.05 (d, 2H,J=12.6 Hz), 7.39-7.50 (m, 12H), 7.57 (d, 2H, J=2.7 Hz), 7.80 (dd, 2H,J=2.1 Hz, 8.4 Hz), 7.90 (s, 2H); ¹³C NMR (75.5 MHz, CDCl₃) δ 44.9, 63.6,69.0, 120.7, 124.2, 128.3, 129.0, 129.3, 129.6, 130.6, 134.1, 134.4,134.6, 135.0, 138.9, 139.0, 162.5, 167.9; MS (FAB, NBA) m/e (relintensity) 833 (M⁺+1, 5).

Bis(8-trimethylsilylacetylenyl-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxy)diethyleneglycol diester 98 (dm-III-94)

A yellow solid (49.5%): mp 205-208° C.; IR (KBr) 3433, 2960, 1730, 1700,1612, 1493, 1255, 1169, 1120, 1071, 847 cm⁻¹; ¹HNMR (300 MHz, CDCl₃) δ0.25 (s, 18H), 3.93 (t, 4H, J=5.4 Hz), 4.04 (d, 2H, J=12.6 Hz), 4.55 (m,4H), 6.04 (d, 2H, J=12.6 Hz), 7.37-7.53 (m, 14H), 7.74 (dd, 2H, J=1.2Hz, 8.4 Hz), 7.91 (s, 2H); ¹³C NMR (75.5 MHz, CDCl₃) δ −0.3, 45.0, 63.6,69.0, 97.5, 102.4, 122.5, 122.7, 128.1, 128.3, 129.0, 129.4, 130.5,134.2, 135.0, 135.1, 135.2, 139.1, 139.3, 162.7, 168.6; MS (FAB, NBA)m/e (rel intensity) 869 (M⁺+1, 100).

Bis(8-acetylenyl-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carb-oxy)diethyleneglycol diester 98 (dm-III-96)

A yellow solid (81.6%): mp 173-177° C.; IR (KBr) 3432, 3280, 1720, 1715,1496, 1254, 1175, 1120, 1074 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 3.12 (s,2H), 3.93 (t, 4H, J=4.5 Hz), 4.06 (d, 2H, J=12.6 Hz), 4.55 (m, 4H), 6.05(d, 2H, J=12.6 Hz), 7.38-7.56 (m, 14H), 7.75 (dd, 2H, J=8.4 Hz, 1.8 Hz),7.91 (s, 2H); ¹³C NMR (75.5 MHz, CDCl₃) δ 45.0, 63.6, 69.0, 79.8, 81.3,121.3, 122.7, 128.1, 128.3, 129.0, 129.3, 130.5, 134.2, 135.2, 135.3,135.6, 139.0, 139.1, 162.6, 168.4; MS (FAB, NBA) m/e (rel intensity) 725(M⁺+1, 63).

The benzodiazepine 100 (bromazepam)^(16,17) was reacted withtrimethylsilyacetylene in the presence of a palladium catalyst toprovide trimethylsilyl analog 101 (Hz157) that was methylated withmethyl iodide/sodium hydride to afford analog 102 (Hz158). This wassubjected to fluoride-mediated desilation to achieve analog 103 (Hz160).

7-Trimethylsilylacetylenyl-5-pyridin-2-yl-1,3-dihydro-benzo[e][1,4]diazepin-2-one(Hz157).

Trimethylsilylacetylenyl analog 101 (Hz157) was obtained in 76% yieldfrom 100 analogous to the procedure employed in [0047] as a light graysolid. mp: 242-243° C.; IR (KBr) 2956, 2155, 1690, 1616, 1492, 1332,1248, 1018, 842, 754 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 0.23 (s, 9H), 4.39(s, 2H), 7.06 (d, 1H, J=8.4 Hz), 7.41 (ddd, 1H, J=7.5, 4.8, 1.2 Hz),7.46 (d, 1H, J=1.8 Hz), 7.57 (dd, 1H, J=8.4, 1.9 Hz), 7.83 (td, 1H,J=7.7, 1.7 Hz), 7.97 (d, 1H, J=7.9 Hz), 8.41 (bs, 1H), 8.68 (d, 1H,J=4.2 Hz); MS (EI) m/e (relative intensity) 334 (35), 333 (M⁺, 100), 332(57), 318 (21), 304 (31).

7-Trimethylsilylacetylenyl-1-methyl-5-pyridin-2-yl-1,3-dihydro-benzo[e][1,4]diazepin-2-one(Hz158).

Trimethylsilyacetylenyl analog 102 (Hz158) was obtained in 74% yieldfrom 101 analogous to the procedure employed in [0048] as a light greysolid. mp: 194-195° C.; IR (KBr) 2956, 2154, 1682, 1614, 1491, 1335,1249, 881, 844, 747 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 0.24 (s, 9H), 3.42(s, 3H), 3.84 (d, 1H, J=10.6 Hz), 4.89 (d, 1H, J=10.6 Hz), 7.29 (d, 1H,J=7.6 Hz), 7.40 (m, 1H), 7.46 (d, 1H, J=1.9 Hz), 7.63 (dd, 1H, J=8.5,1.9 Hz), 7.84 (td, 1H, J=7.7, 1.7 Hz), 8.09 (d, 1H, J=7.9 Hz), 8.68 (d,1H, J=4.3 Hz); MS (EI) m/e (relative intensity) 348 (28), 347 (M⁺, 100),346 (44), 318 (34), 291 (23).

7-Acetylenyl-1-methyl-5-pyridin-2-yl-1,3-dihydro-benzo[e][1,4]diazepin-2-one(Hz160).

The 7-acetyleno analog 103 (Hz160) was obtained in 63% yield from 102analogous to the procedure employed in [0048] as a white solid. mp:190-191° C.; IR (KBr) 3286, 3233, 1678, 1614, 1491, 1344, 1126, 750cm⁻¹; ¹HNMR (300 MHz, CDCl₃) δ 3.07 (s, 1H), 3.86 (d, 1H, J=10.6 Hz),4.93 (d, 1H, J=10.2 Hz), 7.32 (d, 1H, J=8.6 Hz), 7.39 (m, 1H), 7.51 (d,1H, J=1.8 Hz), 7.65 (dd, 1H, J=8.5, 1.9 Hz), 7.83 (td, 1H, J=7.7, 1.7Hz), 8.11 (d, 1H, J=7.9 Hz), 8.65 (d, 1H, J=4.7 Hz); MS (EI) m/e(relative intensity) 275 (M⁺, 100), 274 (35), 246 (43), 219 (30).

The benzodiazepine 100 (bromazepam) was reacted withdiethylphosphorochloridate, followed by the addition of ethylisocyanoacetate to provide the ester 104. This was then reacted withtrimethylsilyacetylene in the presence of a palladium catalyst toprovide trimethylsilyl analog 105 (Hz165) which was subjected tofluoride-mediated desilylation to furnish analog 106 (Hz166).

8-Trimethylsilylacetylenyl-6-pyridin-2-yl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylicacid ethyl ester 105 (Hz165)

Trimethylsilyacetylenyl analog 105 (Hz165) was obtained in 73% yieldfrom 104 analogous to the procedure employed in [0047] as a white solid.mp: 205-206° C.; ¹H NMR (300 MHz, CDCl₃) δ 0.25 (s, 9H), 1.44 (t, 3H,J=7.1 Hz), 4.14 (d, 1H, J=11.0 Hz), 4.44 (m, 2H), 6.11 (d, 1H, J=10.9Hz), 7.38 (ddd, 1H, J=7.5, 4.8, 1.1 Hz), 7.51 (s, 1H), 7.54 (d, 1H,J=8.4 Hz), 7.74 (dd, J=8.3, 1.8 Hz), 7.83 (td, 1H, J=7.7, 1.7 Hz), 7.93(s, 1H), 8.05 (m, 1H), 8.61 (m, 1H).

8-Acetylenyl-6-pyridin-2-yl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylicacid ethyl ester 106 (Hz166).

The 7-acetyleno analog 106 (Hz166) was obtained in 98% yield from 105analogous to the procedure employed in [0048] as a white solid. mp:243-244° C.; ¹H NMR (300 MHz, CDCl₃) δ 1.45 (t, 3H, J=7.1 Hz), 3.17 (s,1H), 4.17 (d, 1H, J=10.0 Hz), 4.45 (m, 2H), 6.13 (d, 1H, J=10.4 Hz),7.38 (ddd, 1H, J=7.5, 4.8, 1.1 Hz), 7.56 (d, 1H, J=8.2 Hz), 7.58 (s,1H), 7.77 (dd, 1H, J=8.6, 1.8 Hz), 7.83 (td, 1H, J=7.7, 1.8 Hz), 7.93(s, 1H), 8.08 (m, 1H), 8.59 (m, 1H).

Some exemplary compounds falling under the scope of the presentinvention are as follows:

In general, any 1,4-benzodiazepine with a 5-phenyl-like substituent inwhich C(7) has been replaced with an acetylene substituent or atrimethylsilyl acetylene substituent or any triazolo benzodiazepine thathas a corresponding substituent at C(8) with a 6-phenyl group(alprazolam numbering system). For example, we claim any benzodiazepinestructurally related to analogs (and other related compounds) todiazepam, alprazolam, medazolam, and triazolam in which the C(7) or C(8)substituent has been replaced with an acetylene ortrimethylsilylacetylene substituent.

Generally, we contemplate all analogs of 1-4 above with X′═F, Cl, Br,NO₂ and/or R″═CH₃, isopropyl, t-butyl, isoxazoles. Also, all analogs ofR—C≡C— with R=t-butyl, isopropyl, cyclopropyl. We believe thatreplacement of the halogen atom in 1,4-benzodiazepines or the relatedtriazolo-1,4-benzodiazepines at C(7) or C(8) generally results inanxiolytic activity with greatly decreased sedative/hypnotic/musclerelaxant activity or, in some cases, no sedative hypnotic activitycompared to known agents.

Experimental MethodsSituational Anxiety Model in Rats

Male Sprague-Dawley rats weighing 180-200 grams were purchased fromCharles River Laboratories (Wilmington, Mass.). The rats were housedindividually in suspended wire cages in a colony room maintained atconstant temperature (21±2° C.) and humidity (50±10%). The room wasilluminated 12 hours per day (lights on at 0600 h). The rats had adlibitum access to food and water throughout the study. Behavioralstudies were conducted between 0600 and 1300 hours. Testing: Amodification of the Defensive Withdrawal procedure, as originallydescribed by Takahashi et al. (1989), was employed. The testingapparatus consisted of an opaque plexiglass open field (106 cm length×92cm width×50 cm height), containing a cylindrical galvanized chamber (14cm length, 10 cm diameter) that was positioned lengthwise against onewall, with the open end 40 cm from the corner. The open field wasilluminated by a 60 watt incandescent bulb, and illumination wastitrated by a powerstat transformer to a 23 lux reading at the entranceto the cylinder. Rats were habituated to handling by gently strokingtheir dorsal surface for approximately one minute daily for 5-6consecutive days before testing. To initiate testing of exploratorybehavior in this unfamiliar environment, each rat was placed within thecylinder, which was then secured to the floor. Behavior was assessed for15 minutes by a trained observer (unaware of treatment assignment) via avideo monitor in an adjacent room. The latency to emerge from thecylinder, defined by the placement of all four paws into the open field,was recorded for each rat. After testing each rat, the plexiglasschamber and the cylinder were cleaned with 1.0% glacial acetic acid toprevent olfactory cues from influencing the behavior of subsequentlytested rats. Drug Administration: All drugs were administered PO 20-60minutes prior to behavioral testing. Data Analysis: Results wereexpressed as the mean±1 SEM. All data were subjected to analysis ofvariance (ANOVA) followed by individual mean comparisons using Fisher'sLeast Significant Difference Test (Kirk, 1968) where appropriate. Thesignificance level was set at p<0.05.

Protection from Pentylenetetrazole-Induced Seizures

Male CF1 mice weighing 20-22 g at the time of the experiment werepurchased from Charles River Laboratories (Wilmington, Mass.).Pentylenetetrazole (Sigma Chemical Co.) was administered at 125 mg/kgs.c. The number of animals surviving was recorded at 30 minutes and 60minutes after administration of pentylenetetrazole. Drug Administration:All drugs were administered PO 60 minutes before administration ofpentyenetetrazole. Data Analysis: The data are presented as the percentof animals protected from death. The data were analyzed by Chi Squarestatistics. The significance level was set at p<0.05.

Protection from Electroshock-Induced Seizures

Male CF1 mice weighing 20-22 g at the time of the experiment werepurchased from Charles River Laboratories (Wilmington, Mass.).Electroshock is administered using a Ugo Basile ECT, Unit 7801 seizureapparatus (Ugo Basile, Italy) and corneal electrodes soaked in 0.9%saline. Mice received a shock of 30 mA for 0.3 seconds. DrugAdministration: All experimental compounds were administered PO 60minutes before administration of electroshock. Data Analysis: The dataare presented as the percent of animals protected from the hind-limbextensor component of the seizure. The data were analyzed by Chi Squarestatistics. The significance level was set at p<0.05.

Open-Field Locomotor Activity in Rats

Male Sprague-Dawley rats, weighing 250-290 grams at the beginning of theexperiment were purchased from Charles River Laboratories (Wilmington,Mass.). The animals were housed in groups of four in a colony roommaintained at constant temperature (21±2° C.) and humidity (50±10%). Theroom was illuminated 12 hours per day (lights on at 0600 h). The ratshad ad libitum access to food and water. The testing apparatus consistedof plexiglas chambers (42×42×30 cm) equipped with Digiscan activitymonitors (Omnitech Electronics, Columbus, Ohio) that detectinterruptions of 16 photobeams spaced 2.5 cm apart and 2.5 cm above thefloor. Horizontal activity was monitored for 60 minutes. DrugAdministration: All drugs were administered PO 20-60 minutes beforebehavioral testing. Data Analysis: Results were expressed as the mean±1SEM. All data were subjected to analysis of variance (ANOVA) followed byindividual mean comparisons using Fisher's Least Significant DifferenceTest (Kirk, 1968) where appropriate. The significance level was set atp<0.05.

Rotorod Performance in Rats

Male Sprague-Dawley rats, weighing 180-200 grams at the beginning of theexperiment were purchased from Charles River Laboratories (Wilmington,Mass.). The animals were housed in groups of four in a colony roommaintained at constant temperature (21±2° C.) and humidity (50±10%). Theroom was illuminated 12 hours per day (lights on at 0600 h). The ratshad ad libitum access to food and water. The degree of musclecoordination or balance (i.e., ataxia) was determined using a standardaccelerating rotorod treadmill (Ugo Basile, Comerio-Varese, Italy orColumbus Instruments, Columbus, Ohio) that was 6 cm in diameter, 24 cmabove the base, and run from an initial speed of 2 rpm to a maximumspeed of 20 rpm. The time each animal remained on the rotating rod wasautomatically recorded, up to a maximum of 5 minutes. Each rat had threepretest acclimation trials, and the latency from the third trial wasused to counterbalance rats for subsequent drug testing. DrugAdministration: All drugs were administered PO 20-60 minutes beforebehavioral testing. Data Analysis: Results were expressed as the mean±1SEM. All data were subjected to analysis of variance (ANOVA) followed byindividual mean comparisons using Fisher's Least Significant DifferenceTest (Kirk, 1968) where appropriate. The significance level was set atp<0.05.

Discriminative Stimulus Effects of Chlordiazepoxide in Rats

Male Sprague-Dawley rats weighing 240 to 300 g at the start of theexperiment were purchased from Charles River Laboratories (Wilmington,Mass.). Animals were housed singly in hanging wire cages in a roommaintained at constant temperature (21-23° C.) and humidity (50±10%) andilluminated 12 hours per day (lights on at 0600 h). Throughout the studyrats were restricted to 12 g of laboratory rodent chow pellets(Bio-Serv, Frenchtown, N.J.) per day, while access to water wasunlimited. All training and testing was done Monday through Friday ofeach week.

Twelve model E10-10 Coulbourn operant chambers (28×26×31 cm) were housedin light-proof, sound-attenuated, and fan-ventilated chambers. Eachoperant chamber was equipped with two non-retractable levers, requiringa downward force equivalent to 15 g (0.15 N), that were mounted 3 cmfrom the side wall, 3 cm above the metal grid floor, and 5 cm from acentrally placed dipper that delivered one 45 mg food pellet (DustlessPrecision Pellets, Bio-Serv, Frenchtown, N.J.). The experimentalchambers were connected to a Micro PDP11/73 computer using a LAB LINCinterface. A SKED-11 operating system (State System, Kalamazoo, Mich.)was used to record and control behavior. Discrimination training: Afterhabituation to the operant chamber, rats were trained to alternate dailybetween response levers on a Fixed Ratio 1 (FR 1) schedule ofreinforcement. Once lever pressing was well established, thereinforcement contingency was increased incrementally to an FR 10schedule, while maintaining the lever alternation. Next, rats weretrained to discriminate between drug (5.0 mg/kg, IP, chlordiazepoxide)and drug vehicle (0.9% saline). Half of the rats were randomly assignedthe left lever as “drug-correct” and the right lever as“saline-correct.” The lever assignments were reversed for the remaininganimals. Every tenth response on the drug-correct lever was reinforcedon days when the rats were pretreated with drug, whereas every tenthresponse on the opposite lever was reinforced after saline injections.In each 2-week period there were 5 drug days and 5 saline days, with theconstraint that there not be more than 3 consecutive drug or vehicledays. Discrimination sessions were continued until each rat reached thecriterion of no more than three incorrect responses before first foodpresentation in 9 out of 10 consecutive sessions. Test sessions: Oncecriterion for testing was met, stimulus substitution tests wereconducted on Friday of each week. Test sessions were 10 minutes induration. During the test sessions, the lever on which the rat firstresponded 10 times resulted in reinforcement and subsequent FR 10reinforcement was made contingent upon pressing this “selected” lever.The lever on which the rat first made 10 responses (the selected lever)and the total number of responses in the session were recorded. OnMonday through Thursday of each week, training sessions were conductedto ensure that criterion for testing was met. If any rat failed to meetthe criterion for testing, testing with that animal was postponed anddiscrimination training continued until the performance criterion wasattained. Data analysis: Drug discrimination results are expressed asthe percentage of animals selecting the chlordiazepoxide-correct lever.

REFERENCES

-   Kirk R E (1968) Experimental Design: Procedures for the Behavioral    Sciences. Brooks/Cole, Belmont, Calif.-   Takahashi L K, Kalin N H, Vanden Burgt J A, Sherman J E (1989)    Corticotropin-releasing factor modulates defensive-withdrawal and    exploratory behavior in rats. Behav Neurosci 103:648-654

Experimental Results

Table 1 (below) shows ratios of lowest effective anxiolytic doses in thesituational anxiety (SA) assay compared with lowest effective dosesproducing side effects in three different models: locomotor activity(LMA), rotorod (RR), and chlordiazepoxide-like subjective effects asmeasured by the drug discrimination method (DD).

Table 2 (below) shows effective doses in a model of epilepsy(pentylenetetrazole-induced seizures) in mice (mg/kg, PO) for QH-ii-066,Xli-JY-DMH, and XHe-ii-053 in comparison with diazepam, triazolam, andDM-1-070.

EXAMPLE 1 Situational Anxiety in Rats

Rats were handled daily for at least 5-6 days. They were then placed ina dark cylinder in an illuminated open field. The time for the rats toexit the dark cylinder was then measured. Vehicle-treated animals remainwithin the dark cylinder for 10-15 minutes (total test duration is 15minutes). This high latency to exit the dark chamber is an index of aheightened state of anxiety. Compounds with anxiolytic efficacy reducelatency to exit the dark chamber. Table 1 shows that QH-ii-066,XLi-JY-DMH, and XHe-ii-053 show anxiolytic effects in the situationalanxiety test at doses>100-fold lower than doses producing sedative andataxic effects (see examples 2 and 3).

EXAMPLE 2 Locomotor Activity in Rats

Rats were placed in an open field and the total distance covered by therat was measured. The test duration was 60 minutes. Compounds producingsedative effects decrease the distance covered. Table 1 shows thatQH-ii-066, XLi-JY-DMH, and XHe-ii-053 are less effective in producingsedative or hypnotic effects than diazepam or triazolam.

EXAMPLE 3 Rotorod Performance in Rats

Rats were placed on a slowly rotating rod and the speed of rotation wasgradually increased. The time on the rod for each rat was recorded.Compounds producing ataxia (motor incoordination) decrease the timespent on the rod compared with vehicle-treated animals. Table 1 showsthat QH-ii-066, XLi-JY-DMH, and XHe-ii-053 are less potent in producingataxia than diazepam or triazolam. Thus, they are likely better drugsclinically because they have decreased side effects [decreased sedation(example 2) and ataxia (example 3)].

EXAMPLE 4 Drug Discrimination in Rats

Animals are taught to emit one response if they just received drug and adifferent response if they just received saline. The animals learn todiscriminate between a “drug state” and a “no drug state”. The rats weretrained to discriminate between a state induced by a typicalbenzodiazepine chlordiazepoxide (CDP; “drug state”) and a state inducedby vehicle (methocel: “no drug state”). Table 1 shows that QH-ii-066,XLi-JY-DMH, and XHe-ii-053 are less potent in producing CDP-like effectsthan diazepam or triazolam and thus may have reduced abuse potentialcompared with CDP.

EXAMPLE 5 Seizure Protection in Mice

Mice treated with certain compounds of the present invention weresubjected to pentylenetetrazole (PTZ) at 125 mg/kg to induce seizures.The percent of animals protected from death within one hour of PTZ wasmeasured. Table 2 shows that QH-ii-066 and XLi-JY-DMH haveanticonvulsant effects against PTZ-induced seizures at doses comparableto those for diazepam and triazolam. Table 2 also shows that XHe-ii-053is effective against PTZ-induced seizures.

TABLE 1 Antianxiety/ Antianxiety/sedation Antianxiety/ataxia abuseliability Diazepam 10 100 5 QH-ii-066 100 >100 30 Triazolam 300 100 30XLi-JY-DMH 10000 10000 1000 DM-i-070 >100 >100 10 XHe-ii-053 >300 >300>300

TABLE 2 PTZ Seizures (mg/kg, PO Diazepam <10 QH-ii-066 <30 Triazolam<1.0 XLi-JY-DMH <1.0 DM-i-070 <100 XHe-ii-053 ≦100

REFERENCES

-   1. Sternbach, L. H.; Fryer, R. I.; Metlesics, W.; Reeder, E.; Sach,    G.; Saucy, G.; Stempel, A. J. Org. Chem. 1962, 27, 3788-3796.-   2. Gu, Q.; Wang, G.; Dominguez, C.; Costa, B. R.; Rice, K. C.;    Skolnick, P. J. Med. Chem. 1993, 36, 1001-1006.-   3. Ning, R. Y.; Fryer, R. I.; Madan, P. B.; Sluboski, B. C. J. Org.    Chem. 1976, 41, 2724-2727.-   4. Liu, R.; Zhang, P.; Skolnick, P.; McKernan, R; Cook, J. M. J.    Med. Chem. 1996, 39, 1928-1934.-   5. Austin, W. B.; Bilow, N.; Kelleghan, W. J.; Lau, K. S. Y. J. Org.    Chem. 1981, 46, 2280-2286.-   6. Sternbach, L. H.; Reeder, E.; Archer, G. A. J. Org. Chem. 1963,    28, 2456-2459.-   7. He, X. Ph.D. Thesis, UW-Milwaukee, 2000.-   8. Heck, R. F. Palladium Reagents in Organic Synthesis; Academic    Press, Orlando, Fla.: Academic Press, 1985.-   9. Bogatskii, A. V.; Andronati, S. A.; Vikhlyaev, Yu. I.;    Voronina, T. A.; Yakubovskaya, L. N.; Ben'ko, A. V. Pharm. Chem. J.    (Engl. Transl.) 1977, 11, 1520-1525-   10. Vejdelek, Zdenek; Protiva, Miroslav. Collect. Czech. Chem.    Commun. 1983, 48, 1477-1482-   11. Hester, J. B.; Ludens, J. H.; Emmert, D. E.; West, B. E. J. Med.    Chem. 1989, 32, 1157-1163.-   12. Fryer, R. I.; Kudzma, L. K; Gu, Z.; Lin, K. J. Org. Chem. 1991,    56, 3715-3719.-   13. Patent, Hoffmann-LaRoche, 1963, DE 1145625.-   14. Patent, Hoffmann-LaRoche, 1958, U.S. Pat. No. 2,893,992.-   15. G. A. Archer and L. H. Sternbach, J. Org. Chem., 29, 231 (1964).-   16. Fryer, R. I.; Zhang, P.; Rios, R. Synth. Commun. 1993, 23,    985-992.-   17. U.S. Pat. No. 3,886,141, 1975.

1. A compound of formula V, or a salt thereof,

wherein: Y and Z are taken together with the two intervening carbonatoms to form a thienyl ring, which is substituted at the C(8) positionwith at least the substituent —C≡C—R, where R is H, Si(CH₃)₃, t-butyl,isopropyl, methyl, or cyclopropyl; R₁ is one of H, CH₃, CF₃, CH₂CF₃,CH₂CH₃, CH₂C≡CH or cyclopropyl; R₂ is a substituted or unsubstituted atleast partially unsaturated 5 membered or 6 membered carbocyclic ring or5 membered or 6 membered heterocyclic ring having at least oneheteroatom selected from N, O and S, wherein if substituted thesubstituent is one or more of F, Cl, Br, or NO₂ at the 2′-position; R₅is a branched or straight chain C₁ to C₄ halogenated or unhalogenatedalkyl or a methyl cyclopropyl.
 2. The compound according to claim 1,wherein said compound is:

wherein R is H or Si(CH₃)₃ R′ is one of ethyl, t-butyl, isopropyl,isoxazole,

 and X′ is H, NO₂, Br, Cl or F.
 3. The compound according to claim 2,wherein R is hydrogen, R′ is ethyl and X′ is H.
 4. The compoundaccording to claim 2, wherein the CO₂R′ is replaced with

wherein R″ is CH₃, CH₂CH₃ or iPr.
 5. A compound of formula VI, or a saltthereof,

wherein: Y and Z are taken together with the two intervening carbonatoms to form a thienyl ring, which is substituted at the C(8) positionwith at least the substituent —C≡C—R, where R is H, Si(CH₃)₃, t-butyl,isopropyl, methyl, or cyclopropyl; R₁ is one of H, CH₃, CF₃, CH₂CH₃,CH₂CF₃, CH₂C≡CH or cyclopropyl; R₂ is a substituted or unsubstituted atleast partially unsaturated 5 membered or 6 membered carbocyclic ring or5 membered or 6 membered heterocyclic ring having at least oneheteroatom selected from N, O and S, wherein if substituted thesubstituent is one or more of F, Cl, Br, or NO₂ at the 2′-position; R₆is a branched or straight chain C₁ to C₄ alkyl or a methyl cyclopropyl.6. A compound of formula IX, or a salt thereof,

wherein: n is 0 to 4; Y and Z are taken together with the twointervening carbon atoms to form a thienyl ring, which is substituted atthe C(8) position with at least the substituent —C≡C—R, where R is H,Si(CH₃)₃, t-butyl, isopropyl, methyl, or cyclopropyl; Y′ and Z′ aretaken together with the two intervening carbon atoms to form a thienylring, which is substituted at the C(8)′ position with at least thesubstituent —C≡C—R′, where R′ is H, Si(CH₃)₃, t-butyl, isopropyl,methyl, or cyclopropyl; R₁ and R₁′ are independently one of H, CH₃, CF₃,CH₂CF₃, CH₂CH₃, CH₂C≡CH or cyclopropyl; R₂ and R₂′ are independently asubstituted or unsubstituted at least partially unsaturated 5 memberedor 6 membered carbocyclic ring or 5 membered or 6 membered heterocyclicring having at least one heteroatom selected from N, O and S, wherein ifsubstituted the substituent is one or more of F, Cl, Br, or NO₂ at the2′-position.
 7. A compound of formula X, or a salt thereof,

wherein: Y and Z are taken together with the two intervening carbonatoms to form a thienyl ring, which is substituted at the C(8) positionwith at least the substituent —C≡C—R, where R is H, Si(CH₃)₃, t-butyl,isopropyl, methyl, or cyclopropyl; Y′ and Z′ are taken together with thetwo intervening carbon atoms to form a thienyl ring, which issubstituted at the C(8)′ position with at least the substituent —C≡C—R′,where R′ is H, Si(CH₃)₃, t-butyl, isopropyl, methyl, or cyclopropyl; R₁and R₁′ are independently one of H, CH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂C≡CH orcyclopropyl; R₂ and R₂′ are independently a substituted or unsubstitutedat least partially unsaturated 5 membered or a 6 membered carbocyclicring or 5 membered or 6 membered heterocyclic ring having at least oneheteroatom selected from N, O and S, wherein if substituted thesubstituent is one or more of F, Cl, Br, or NO₂ at the 2′-position; B isO or NH and wherein —BCH₂B— is optionally replaced with —N(R₇)—N(R₇)—,where R₇ is one of H, CH₃, alkyl, or cycloalkyl.
 8. A compound offormula XI, or a salt thereof,

wherein: n is 1 or 2 Y and Z are taken together with the two interveningcarbon atoms to form a thienyl ring, which is substituted at the C(8)position with at least the substituent —C≡C—R, where R is H, Si(CH₃)₃,t-butyl, isopropyl, methyl, or cyclopropyl; Y′ and Z′ are taken togetherwith the two intervening carbon atoms to form a thienyl ring, which issubstituted at the C(8)′ position with at least the substituent —C≡C—R′,where R′ is H, Si(CH₃)₃, t-butyl, isopropyl, methyl, or cyclopropyl; R₁and R₁′ are independently one of H, CH₃, CF₃, CH₂CH₃, CH₂CF₃, CH₂C≡CH orcyclopropyl; R₂ and R₂′ are independently a substituted or unsubstitutedat least partially unsaturated 5 membered or 6 membered carbocyclic ringor 5 membered or 6 membered heterocyclic ring having a heteroatomselected from N, O and S, wherein if substituted the substituent is oneor more of F, Cl, Br, or NO₂ at the 2′-position; B is O, NH, or—N(R₇)—N(R₇)—, where R₇ is one of H, CH₃, alkyl, or cycloalkyl.